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Clin Pharmacokinet 2005; 44 (1): 61-98
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REVIEW ARTICLE
 2005 Adis Data Information BV. All rights reserved.
Pharmacokinetics and
Pharmacodynamics of Systemically
Administered Glucocorticoids
David Czock, Frieder Keller, Franz Maximilian Rasche and Ulla Häussler
Division of Nephrology, University Hospital Ulm, Ulm, Germany
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
1. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
1.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
1.1.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
1.1.2 Metabolism and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
1.2 Selected Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
1.2.1 Cortisol, Cortisone, and Hydrocortisone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
1.2.2 Prednisolone and Prednisone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
1.2.3 Methylprednisolone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
1.2.4 Dexamethasone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
1.3 Pharmacokinetic Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
1.3.1 Influence of Other Drugs on Glucocorticoid Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . 68
1.3.2 Influence of Glucocorticoids on the Pharmacokinetics of Other Drugs . . . . . . . . . . . . . . . . 69
1.3.3 Interactions Between Glucocorticoids and Ciclosporin, Tacrolimus or Sirolimus
(Rapamycin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
1.4 Influence of Diseases on Glucocorticoid Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
2. Genomic and Nongenomic Mechanisms of Glucocorticoid Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
2.1 Genomic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
2.1.1 Glucocorticoid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
2.1.2 Glucocorticoid Response Elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
2.1.3 Transcription Factors (Nuclear Factor κB and Activator Protein 1) . . . . . . . . . . . . . . . . . . . . 73
2.1.4 Post-Transcriptional and Translational Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
2.2 Nongenomic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
2.2.1 Specific Nongenomic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
2.2.2 Nonspecific Nongenomic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
3. The Host Defence Response and the Effects of Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
3.1 Molecular Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
3.1.1 Cytokines and Chemokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.1.2 Inflammatory Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.2 Cellular Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.2.1 Cell Trafficking and Adhesion Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.2.2 T Cell Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.2.3 Cell Proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.2.4 Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.2.5 Basement Membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.3 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
62
Czock et al.
3.4 Immune Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
4. Adverse Effects of Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
5. Pharmacodynamics of Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
5.1 Biomarker and Surrogate Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
5.2 Potency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
5.3 Clinical Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
5.4 Pharmacodynamic Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
6. Pharmacokinetic/Pharmacodynamic Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
6.1 Pharmacokinetic/Pharmacodynamic Analysis of Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . 82
6.2 In Vivo Potency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
6.3 Selected Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
6.3.1 Influence of Sex on Glucocorticoid Pharmacokinetic/Pharmacodynamic Properties . . . 84
6.3.2 Influence of Age on Glucocorticoid Pharmacokinetic/Pharmacodynamic Properties 84
6.3.3 Once- Versus Twice-Daily Glucocorticoid Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
6.3.4 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
7. Clinical Aspects of Glucocorticoid Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
7.1 Glucocorticoid Pulse Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
7.1.1 Emergency Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
7.1.2 Non-Emergency Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
7.2 Diseases Not Treated with Pulse Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
7.3 Role of the Dosage Interval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
7.4 Variation in Clinical Response to Glucocorticoid Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Abstract
Glucocorticoids have pleiotropic effects that are used to treat diverse diseases
such as asthma, rheumatoid arthritis, systemic lupus erythematosus and acute
kidney transplant rejection. The most commonly used systemic glucocorticoids
are hydrocortisone, prednisolone, methylprednisolone and dexamethasone. These
glucocorticoids have good oral bioavailability and are eliminated mainly by
hepatic metabolism and renal excretion of the metabolites. Plasma concentrations
follow a biexponential pattern. Two-compartment models are used after intravenous administration, but one-compartment models are sufficient after oral administration.
The effects of glucocorticoids are mediated by genomic and possibly nongenomic mechanisms. Genomic mechanisms include activation of the cytosolic
glucocorticoid receptor that leads to activation or repression of protein synthesis,
including cytokines, chemokines, inflammatory enzymes and adhesion molecules. Thus, inflammation and immune response mechanisms may be modified.
Nongenomic mechanisms might play an additional role in glucocorticoid pulse
therapy.
Clinical efficacy depends on glucocorticoid pharmacokinetics and pharmacodynamics. Pharmacokinetic parameters such as the elimination half-life, and
pharmacodynamic parameters such as the concentration producing the halfmaximal effect, determine the duration and intensity of glucocorticoid effects.
The special contribution of either of these can be distinguished with pharmacokinetic/pharmacodynamic analysis. We performed simulations with a pharmacokinetic/pharmacodynamic model using T helper cell counts and endogenous cortisol
 2005 Adis Data Information BV. All rights reserved.
Clin Pharmacokinet 2005; 44 (1)
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
63
as biomarkers for the effects of methylprednisolone. These simulations suggest
that the clinical efficacy of low-dose glucocorticoid regimens might be increased
with twice-daily glucocorticoid administration.
Glucocorticoids have pleiotropic effects and they
are used frequently and intensively in clinical practice for many different indications. Their anti-inflammatory effect is used in inflammatory diseases
(e.g. asthma and rheumatoid arthritis) and their immunosuppressive effect is used in autoimmune diseases (e.g. systemic lupus erythematosus [SLE]) as
well as in organ transplantation (e.g. acute kidney
transplant rejection). Clinically applied dosage regimens have been derived empirically and there is
considerable variability between patients in clinical
response to glucocorticoid treatment. The pharmacokinetics and pharmacodynamics of glucocorticoids have therefore been evaluated in many studies.
Generally, the indications for glucocorticoids can
be divided into two categories. The first category
includes emergency situations such as acute kidney
transplant rejection or diffuse alveolar haemorrhage
due to autoimmune diseases. In these patients, high
doses of glucocorticoids are usually administered
intravenously. The second category includes chronic
diseases such as rheumatoid arthritis or the nephrotic syndrome. In these patients, low-dose maintenance therapy with glucocorticoids is given orally
using the lowest active dose in order to limit severe
long-term adverse events. What is the rationale behind these opposing practices, how might this be
explained, and how might it be improved?
Pharmacokinetic/pharmacodynamic modelling
allows simultaneous analysis of pharmacokinetics
and pharmacodynamics[1-4] and to distinguish their
respective contribution to clinical efficacy. This
might help to improve dosage regimens for glucocorticoids, such as intravenous pulse administration
or low-dose administration of twice-daily dose fractions.
This article aims to review and discuss the relationship between pharmacokinetics, molecular
 2005 Adis Data Information BV. All rights reserved.
mechanisms, pharmacodynamics, and clinical experience with systemically administered glucocorticoids.
1. Pharmacokinetics
1.1 General
The pharmacokinetic characteristics of the various glucocorticoids depend on their physicochemical properties.[5] Glucocorticoids are lipophilic and
are usually administered as prodrugs when given
intravenously. Preparations include the hydrophilic
phosphate and succinate esters of glucocorticoids,
which are converted within 5–30 minutes to their
active forms.[6-8] Small doses of glucocorticoids can
also be administered as an alcoholic solution.[9-11]
1.1.1 Absorption and Distribution
Glucocorticoids are well absorbed after oral administration and have a bioavailability of 60–100%
(table I).[9,12-20] They have moderate protein binding
and a moderate apparent volume of distribution. The
pharmacokinetics of hydrocortisone (i.e. cortisol)
and prednisolone are nonlinear. Both bind to the
glycoprotein transcortin (i.e. corticosteroid binding
globulin) and albumin.[21-23] Transcortin has a high
affinity and a low capacity for hydrocortisone and
prednisolone, whereas albumin has a low affinity
but high capacity. This leads to an increase in the
free glucocorticoid fraction once transcortin is saturated at concentrations of about 400 µg/L. Such
concentrations are achieved after administration of
hydrocortisone or prednisolone doses >20mg.
Protein binding is biologically relevant, because
only free drug can reach the biophase (i.e. the site of
action) and interact with the receptor. Therefore,
pharmacodynamic considerations have to include
protein binding. Clinically, decreased protein bindClin Pharmacokinet 2005; 44 (1)
Drug
ROA Conc. F
(%)
Cortisol
Cmax
(µg/L/1mg
dose)a
tmax
(h)
t1/2
(h)
Vd
(L)b
Vd/F
(L)b
CL
(L/h)b
CL/F
(L/h)b
Total
Hydrocortisoned
IV
PO
Total
Prednisolone
phosphate
IV
Total
Prednisolone after IV
prednisolone
phosphate
Total
2.0 ± 0.3 27 ± 7
(1.7–2.1) (24–39)
96 ± 20 15.3 ± 2.9
88.3 ± 24.0
0.08
3.7 ± 1.1
(2.9–6.7)
Prednisolone
succinate
IV
Total
Prednisolone after IV
prednisolone
succinate
Total
Prednisolone
Total
32 ± 4
45 ± 5
(39–50)
0.35 ± 0.08
(0.20–0.48)
9±2
(5–16)
141 ± 44
(95–212)
48 ± 15
(20–63)
67 ± 23
(57–81)
99 ± 8
92 ± 2
(92–93)
73 ± 4 18.0 ± 6.6
(70–76) (10.3–24.4)
0.43 ± 0.11
0.22 ± 0.03
(0.19–0.27)
0.27 ± 0.06
(0.13–0.36)
50 ± 12
(44–59)
60 ± 28
(30–132)
Free
4.3 ± 2.8
(3.4–5.2)
1.5 ± 0.7 2.5 ± 1.0
(1.4–1.5) (2.2–2.9)
302 ± 210
(254–350)
PO
Total
84 ± 13 2.4 ± 1.1
(2.2–2.5)
2.6 ± 1.3 3.3 ± 1.3
(2.5–2.8) (2.9–4.1)
Prednisolone after PO
prednisone
Total
79 ± 14 16.6 ± 4.8
(62–99) (9.8–22.6)
1.9 ± 1.1 3.0 ± 0.8
(1.3–3.0) (1.7–4.2)
Free
53 ± 10 4.2 ± 1.1
2.0 ± 0.4
(1.6–2.6)
0.25 ±
24 ± 6
0.10
(23–25)
(0.07–0.37)
12 ± 3
(11–14)
67 ± 19
(46–91)
2.01 ± 0.48
4.9
13 ± 4
(8–23)
13.7 ± 4.2 0.19 ± 0.06
(12.1–14.9) (0.19–0.20)
86 ± 6
81 ± 42
(77–85)
2.0 ± 2.5
(1.2–3.5)
0.26 ± 0.07
(0.19–0.32)
1.1
0.31 ± 0.10
(0.27–0.36)
2.4 ± 1.0
(1.6–2.0)
43 ± 12
(31–48)
62 ± 9
(55–65)
170 ± 54
(110–235)
12 ± 2
(7–14)
10.2 ± 3.5 3.9 ± 4.2
(4.3–14.1) (1.3–9.7)
72 ± 15
(38–97)
27 ± 8.2
90 ± 27
(24.5–28.7) (82–97)
0.29 ± 0.11
(0.19–0.32)
6.0 ± 6.2
(3.2–9.7)
9.2
(8.3–9.8)
Continued next page
Czock et al.
Clin Pharmacokinet 2005; 44 (1)
Total
18 ± 4
40 ± 9
(19–80)
26 ± 13
1.3 ± 0.7 3.2 ± 1.0
(0.9–1.6) (2.7–4.1)
Methylprednisolone IV
succinate
ke
(h–1)
3.3 ± 1.4
(2.1–5.3)
18.1 ± 5.5
(7.6–30.7)
PO
kac
(h–1)
1.4 ± 0.9
3.0 ± 0.4
(2.3–3.8)
2.2 ± 0.3
(1.7–2.7)
Total
fren
(%)
1.2 ± 0.4 1.8 ± 0.5
Free
IV
PB
(%)
94
Total
Prednisone after
prednisolone
phosphate
Prednisone
Vss
(L)b
64
 2005 Adis Data Information BV. All rights reserved.
Table I. Glucocorticoid pharmacokinetics after systemic administration. The pooled mean ± pooled standard deviation (see Appendix) and the range of the primary mean values
(minimum–maximum) are given for cases where more than one study was found[3,6,7,9-20,22,24-71]
Drug
ROA Conc. F
(%)
Cmax
(µg/L/1mg
dose)a
tmax
(h)
t1/2
(h)
8.3 ± 3.3
(6.3–10.7)
0.8
2.4 ± 0.6
(1.7–3.2)
Vd
(L)b
Methylprednisolone IV
after
methylprednisolone
succinate
Total
Methylprednisolone IV
phosphate
Total
0.06 ±
0.01
(0.06–0.07)
Methylprednisolone IV
after
methylprednisolone
phosphate
Total
3.0 ± 1.7
(3.0–3.1)
Methylprednisolone PO
Total
88 ± 23 8.2 ± 2.4
(82–91) (4.6–10.4)
2.1 ± 0.7 2.5 ± 1.2
(1.5–3.1) (1.6–3.4)
Vd/F
(L)b
Vss
(L)b
75 ± 16
(55–95)
90 ± 23
(57–123)
6.1 ± 2.1
(5.9–6.4)
CL
(L/h)b
CL/F
(L/h)b
PB
(%)
24 ± 7 78 ± 2 3.6
(13–33) (75–82) (3.3–3.9)
66 ± 21
(53–78)
100 ± 45
(74–134)
26 ± 8
(19–37)
1.3
Methylprednisone
in vitro
75 ± 3
3.6 ±
1.2
Total
Dexamethasone
IV
after
dexamethasone
sodium phosphate
Total
90
Dexamethasone
Total
76 ± 10 8.4 ± 3.6
(61–86)
PO
10.5 ± 2.8
(10.2–10.8)
4.6 ± 1.2
(4.1–5.4)
28 ± 7
65.7 ±
17.3
(27.0–98)
81.6 ±
16.6
(61.2–98)
0.28 ± 0.07
(0.19–0.41)
1.7 ± 0.5
0.27 ± 0.08
(0.23–0.31)
7.7 ± 1.6
12 ± 4
(5–21)
9.9 ± 18.6 0.21 ± 0.03
(4.0–12.4) (0.20–0.23)
1.5
4.0 ± 0.9
(1.0–2.0)
Dexamethasone
in vitro
5.6 ± 3.5
(3.1–9.5)
0.28 ± 0.06
(0.23–0.33)
4.9 ± 1.5
(3.1–6.6)
79 ± 3
ke
(h–1)
11.4 ± 2.5
(10.1–12.7)
24 ± 8
(23–24)
109 ± 32
(96–125)
kac
(h–1)
1.2 ± 0.4
76.3 ±
71.5 ±
12.8
13.9
(60.8–91.8) (55.5–87.5)
Methylprednisolone
in vitro
Dexamethasone
IV
sodium phosphate
fren
(%)
0.16
75 ± 4
Cmax was normalised to a glucocorticoid dose of 1mg. Multiply by 10–6/MW to convert from µg/L to mol/L. MW of hydrocortisone = 362.5Da, prednisolone = 360.5Da,
prednisone = 358.4Da, methylprednisolone = 374.5Da and dexamethasone = 392.5Da.
b
Volume and clearance parameters were normalised to 70kg bodyweight.
Formation rate constant kf in the case of conversion after intravenous administration of a prodrug.
d
Parameter only for low doses (= 20mg) of hydrocortisone available.
CL = total clearance; CL/F = apparent clearance; Cmax = peak plasma concentration; Conc. = plasma concentration measured; F = fraction in % of the administered dose
systemically available; Free = unbound to plasma components; fren = renally excreted fraction in % of unchanged drug; IV = intravenous; ka =absorption rate constant; ke =
elimination rate constant; MW = molecular weight; PB = plasma binding; PO = orally; ROA = route of administration; tmax = time to reach Cmax; t1/2 = terminal half-life; Total =
plasma bound and free; Vd = volume of distribution; Vd/F = apparent volume of distribution; Vss = volume of distribution at steady state.
65
Clin Pharmacokinet 2005; 44 (1)
a
c
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
 2005 Adis Data Information BV. All rights reserved.
Table I. Contd
66
Czock et al.
ing due to low plasma albumin concentrations correlated with glucocorticoid adverse effects in prednisone therapy.[72] Generally, however, alterations in
protein binding do not have much impact on drug
action.[73]
1.1.2 Metabolism and Excretion
The renal excretion of unchanged glucocorticoids is only 1–20% (table I).[6,7,14,17,24-27] Glucocorticoid metabolism is a two-step process. Firstly,
oxygen or hydrogen atoms are added then secondly,
conjugation takes place (glucuronidation or sulphation). Subsequently the kidney excretes the resulting
hydrophilic inactive metabolites.
Intracellular metabolism by 11β-hydroxysteroid
dehydrogenase (11β-HSD) controls the availability
of glucocorticoids for binding to the glucocorticoid
and mineralocorticoid receptors. Type 1 dehydrogenase (11β-HSD1) is widely distributed in glucocorticoid target tissues and has its highest activity in the
liver. 11β-HSD1 acts mainly as a reductase, converting the inactive cortisone to the active cortisol.[74,75] Type 2 dehydrogenase (11β-HSD2) is
found in mineralocorticoid target tissues (kidney,
colon, salivary glands, placenta). 11β-HSD2 has a
high affinity for endogenous cortisol and by oxidation, converting cortisol to cortisone, it protects the
mineralocorticoid receptor from occupation by cortisol.[76] The activity of 11β-HSD2 varies depending
on the type of glucocorticoid,[75,76] which explains to
some extent the different mineralocorticoid activities of different glucocorticoids.
The undesired mineralocorticoid effects of glucocorticoid treatment should be pronounced when
the capacity of 11β-HSD2 is exceeded. Therefore,
we speculate that the mineralocorticoid effects of
glucocorticoids might depend on the administration
scheme. A low glucocorticoid dose leading to concentrations just above the protective capacity of
11β-HSD2 would be expected to have reduced
mineralocorticoid effects when administered as two
dose fractions, because both concentration peaks
would not exceed 11β-HSD2 capacity. In contrast,
higher glucocorticoid doses, exceeding the 11β 2005 Adis Data Information BV. All rights reserved.
HSD2 capacity and even leading to saturation of the
mineralocorticoid receptor, would be expected to
have enhanced mineralocorticoid effects when administered as two dose fractions, because the total
time when mineralocorticoid receptors are occupied
would be prolonged.
1.2 Selected Examples
1.2.1 Cortisol, Cortisone, and Hydrocortisone
Cortisol is the active hormone produced by adrenal synthesis and secreted after stimulation by the
pituitary hormone ACTH. Daily cortisol production
is about 10mg in healthy volunteers[77] and can
increase up to 400mg in conditions of severe
stress.[78] Endogenous cortisol concentrations show
a circadian pattern, with high concentrations in the
morning between 6:00am and 9:00am (about 160
µg/L at 8:00am in healthy volunteers) and low concentrations in the evening between 8:00pm and
2:00am. Cortisol is metabolised to the inactive cortisone and further to dihydrocortisone and tetrahydrocortisone. Other metabolites include dihydrocortisol, 5α-dihydrocortisol, tetrahydrocortisol and 5αtetrahydrocortisol. The biological activity of the latter metabolites is unclear.[79,80] After suppression of
cortisol secretion by exogenous glucocorticoids,
cortisol concentrations decline rapidly. Biexponential functions are used to describe this cortisol decline after prednisolone[28,29] whereas monoexponential functions are used for the cortisol decline
after methylprednisolone.[30,31]
Hydrocortisone is chemically identical to cortisol, but this name is used in order to distinguish
drug administration from endogenous production.
Hydrocortisone is well absorbed after oral administration[9] and the disposition is biexponential.[81] The
pharmacokinetic parameters of cortisol and hydrocortisone are summarised in table I.
1.2.2 Prednisolone and Prednisone
Prednisolone (dehydrocortisol) is the active substance, whereas the inactive prednisone (dehydrocortisone) is activated by 11β-HSD1 to prednisoClin Pharmacokinet 2005; 44 (1)
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
67
Table II. Dose-dependent pharmacokinetics of prednisolone, as shown for total concentration of prednisolone after oral administration. The
pooled mean ± pooled standard deviation (see Appendix) and the range of the primary mean values (minimum–maximum) are given for
cases where more than one study was found[19,32,35,36,53,60,67,70,71]
Cmax (µg/L/
1mg dose)a
tmax (h)
t1/2 (h)
Vd/F (L)b
Vss (L)b
CL/F (L/h)b ka (h–1)
ke (h–1)
Prednisolone
(≤20mg)
20.7 ± 6.5
(16.2–30.7)
1.3 ± 0.8
(1.0–1.5)
3.0 ± 1.0
(2.7–3.7)
42 ± 16
(30–43)
54 ± 16
(46–63)
10 ± 3
(8–14)
1.8 ± 2.1
(1.4–3.5)
0.28 ± 0.08
(0.21–0.32)
Prednisolone
(25–60mg)
16.3 ± 3.5
(11.7–21.1)
1.3 ± 0.6
(0.9–1.6)
3.0 ± 0.6
(2.7–3.6)
64 ± 13
(51–74)
91 ± 24
15 ± 4
(13–18)
2.2 ± 2.8
(1.2–3.2)
0.25 ± 0.06
(0.22–0.28)
11.1 ± 6.0
(7.6–12.3)
1.5 ± 0.5
4.0 ± 1.4c
(3.7–4.1)
98 ± 54
(87–132)
Drug
Prednisolone
(100mg)
F (%)
99 ± 8
17 ± 7
(15–23)
0.19 ± 0.07
a
Cmax was normalised to a prednisolone dose of 1mg.
b
Volume and clearance parameters were normalised to 70kg bodyweight.
c
There were no significant differences between the half-lives after high and low dose prednisolone in the primary studies.
CL/F = apparent clearance; Cmax = peak plasma concentration; F = fraction in % of the administered dose systemically available; ka =
absorption rate constant; ke = elimination rate constant; t1/2 = terminal half-life; tmax = time to reach Cmax; Vd/F = apparent volume of
distribution; Vss = volume of distribution at steady state.
lone.[76] Similar to cortisone/cortisol, there is interconversion between both substances. The recycled
proportion of prednisone has been estimated at
76%.[14]
The pharmacokinetics of prednisolone and prednisone are complicated by dose-dependency due to
nonlinear protein binding.[24,32] Protein binding of
prednisolone decreases nonlinearly from 95% to
60–70%, while the concentration increases from 200
µg/L to 800 µg/L when protein binding of prednisolone reaches a plateau.[18,24,33,34,82] In consequence, a
dose-dependent increase in the volume of distribution (Vd) and drug clearance (CL) is observed at
doses over 20mg (table II).[19,32,35,83] However, the
elimination half-life remains constant[19,32] and the
dose dependencies of Vd and CL disappear when
free prednisolone concentrations are measured.[18,35]
Prednisolone clearance decreases again only at very
high doses, which can be explained by saturation of
elimination mechanisms.[27] The affinity of prednisone for transcortin is 10-fold lower than that of
prednisolone.[82] Prednisolone metabolites include
6β-hydroxyprednisolone and 20β-hydroxyprednisolone.[14,24] The disposition of prednisolone is
biexponential. A two-compartment model is appropriate for intravenous administration.[27,29] One- and
two-compartment models can be used with oral administration.[28,36,84] The pharmacokinetic para 2005 Adis Data Information BV. All rights reserved.
meters of prednisolone and prednisone are summarised in table I.
1.2.3 Methylprednisolone
Methylprednisolone (6α-methylprednisolone)
has no affinity for transcortin and binds only to
albumin.[37,38] Accordingly, methylprednisolone
pharmacokinetics are linear, with no dose-dependency.[7,35] Methylprednisolone has many metabolites, including 20-carboxymethylprednisolone and
6β-hydroxy-20α-hydroxymethylprednisolone. Interconversion between methylprednisolone and
methylprednisone has been described.[37,39] The disposition of methylprednisolone is biexponential.[7,17]
A two-compartment model is appropriate for intravenous administration of very high doses.[17] A onecompartment model can be used with lower intravenous doses[30,40] and oral administration.[36] The
pharmacokinetic parameters of methylprednisolone
are summarised in table I.
1.2.4 Dexamethasone
Dexamethasone
(9α-fluoro-16α-methylprednisolone) has no affinity for transcortin and binds
only to albumin.[41] The pharmacokinetics of dexamethasone after intravenous administration are linear.[11,42] A second peak after intravenous administration can be explained by enterohepatic recirculation.[20,43] The disposition of dexamethasone is
biexponential[42,44] and a two-compartment model is
Clin Pharmacokinet 2005; 44 (1)
68
Czock et al.
Table III. Interactions of drugs and influence of diseases on glucocorticoid pharmacokinetics. The values are expressed as a percentage of
the value without drug coadministration or disease (which was set at 100%) from the respective study[10,12,22,26,29,30,33,39,45-52,54,55,85,88-92]
Drug
Prednisolone
Methylprednisolone
Dexamethasone
CL/F (%)
t1/2 (%)
CL/F (%)
t1/2 (%)
CL/F (%)
Phenobarbital
(phenobarbitone)
140
80
300
45
Carbamazepine
180
65
440
45
Phenytoin
180
70
580
30
Rifampicin (rifampin)
140
60
Ketoconazole
Unchanged
Unchanged
Itraconazole
Unchanged
Unchanged
Diltiazem
83
115
t1/2 (%)
40–50
170
67
30
300
145
Troleandomycin
190
Erythromycin
Prolonged
Clarithromycin
Unchanged
Ciclosporin
Decreased
Unchanged
35
Unchanged
Unchanged
Sirolimus (rapamycin)
130
Grapefruit juice
Unchanged
230
130
Disease
Renal failure
60
150
Chronic liver disease
Reduced
CL/F = apparent clearance; t1/2 = terminal half-life.
Unchanged
Unchanged
165
70
Unchanged
Unchanged
65
170
appropriate for intravenous dexamethasone.[43,44]
The pharmacokinetic parameters of dexamethasone
are summarised in table I.
1.3 Pharmacokinetic Drug-Drug Interactions
1.3.1 Influence of Other Drugs on
Glucocorticoid Pharmacokinetics
Coadministration of enzyme inducers (e.g. barbiturates, carbamazepine, phenytoin, rifampicin [rifampin]) increases the clearance and decreases the
half-life of prednisolone and methylprednisolone
(table III).[85] A study of the time course of induction
with rifampicin showed that the changes in pharmacokinetics of prednisolone were maximal 2 weeks
after the start, and were normal again 2 weeks after
the end of rifampicin therapy.[45] The clinical relevance of such interactions was demonstrated in patients with kidney transplants treated with prednisone. A lower kidney transplant survival rate was
found in those patients receiving concomitant anticonvulsants (phenobarbital [phenobarbitone]/
diphenylhydantoin).[86] This can be explained by a
reduced immunosuppressive effect due to increased
 2005 Adis Data Information BV. All rights reserved.
prednisolone elimination. In another study, the loss
of kidney transplant function was associated with
rifampicin treatment.[87]
Coadministration of cytochrome P450 (CYP)
3A4 inhibitors (e.g. ketoconazole, clarithromycin)
decreases the clearance and increases the half-life of
methylprednisolone and dexamethasone, whereas
prednisolone is usually not affected (table
III).[12,26,29,30,46-49] Decreased clearance of glucocorticoids can lead to increased effects (biomarker:
lymphocytes, cortisol).[30,39,47,50,51,93-95] Clinically,
macrolides have been used as glucocorticoid-sparing agents in patients with glucocorticoid-dependent
asthma.[96,97] However, short-term administration of
macrolides does not need a dose reduction of glucocorticoids. Cimetidine had no influence on the
pharmacokinetics of prednisolone[83,98] or methylprednisolone in one patient.[99] Grapefruit juice increased the half-life of oral methylprednisolone[52]
but did not affect prednisolone.[88]
Users of oral contraceptives (OCs) have higher
concentrations[53] and a lower clearance[34] of prednisolone, which has been explained by increased
Clin Pharmacokinet 2005; 44 (1)
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
transcortin levels.[34] Methylprednisolone has a lower clearance in OC users,[40] which has been explained by inhibition of oxidative processes by OCs.
This lower clearance of methylprednisolone, however, was associated with mixed changes in
glucocorticoid effects, and it was concluded that a
change in methylprednisolone dose is not necessary
in OC users.[40]
In vitro and animal studies suggest that cortisol,
prednisolone, methylprednisolone, and dexamethasone are substrates of P-glycoprotein.[100-102] Therefore, coadministration of P-glycoprotein inhibitors
could increase glucocorticoid absorption and might
affect glucocorticoid distribution. Oral coadministration of valspodar increased the area under the
curve (AUC) of dexamethasone 1.24 times in
healthy volunteers, although it is most likely that
this is not clinically relevant.[103]
Smoking did not affect the pharmacokinetics of
prednisolone or dexamethasone.[104]
1.3.2 Influence of Glucocorticoids on the
Pharmacokinetics of Other Drugs
Glucocorticoids affect the pharmacokinetics of
other drugs by enzyme induction (e.g. of cytochromes,[105] P-glycoprotein or glucuronosyltransferase). Dexamethasone induced CYP3A4 at high
doses (16–24 mg/day)[106] but not at low doses (1.5
mg/day).[107] Methylprednisolone at a daily dose of
8mg did not induce CYP3A4 in healthy volunteers.[108] Autoinduction has been used to explain a
time-dependent increase in the prednisolone[35] and
methylprednisolone[109] clearance. P-glycoprotein
might be induced by lower glucocorticoid doses.
Dexamethasone induced P-glycoprotein at low
doses and CYP at high doses, as shown in rats.[110]
The clinical importance of enzyme induction by
glucocorticoids is largely unknown. A dose reduction of phenytoin was necessary in a patient after
discontinuing dexamethasone therapy.[111]
Mycophenolate concentrations increase after
methylprednisolone withdrawal in patients with kidney transplants.[112] Mycophenolate is metabolised
by glucuronosyltransferase and decreasing glucuro 2005 Adis Data Information BV. All rights reserved.
69
nosyltransferase induction after methylprednisolone
withdrawal could explain increased mycophenolate
concentrations. Induction of glucuronosyltransferase expression by glucocorticoids was demonstrated
in vitro.[113]
1.3.3 Interactions Between Glucocorticoids and
Ciclosporin, Tacrolimus or Sirolimus (Rapamycin)
The interactions between ciclosporin and glucocorticoids are complicated and there are studies with
conflicting results. Both ciclosporin and glucocorticoids are substrates of CYP[12,30] and possibly Pglycoprotein.[100] Ciclosporin inhibits P-glycoprotein, whereas glucocorticoids might induce P-glycoprotein and CYP.[106,110]
Ciclosporin affects the pharmacokinetics of prednisolone. The AUC of prednisolone after oral prednisone was higher,[89] and the oral clearance of prednisolone was lower[90] in patients receiving ciclosporin. In addition, the oral clearance of
prednisolone increased in patients who were
switched to a ciclosporin-free regimen and decreased when ciclosporin was added.[90] This might
be explained at least partially by increased absorption of prednisolone due to P-glycoprotein inhibition by ciclosporin. In contrast, another study did
not find changes in the pharmacokinetics of prednisolone with ciclosporin coadministration.[114] However, the latter study was performed in patients only
1 month after transplantation and it is possible that
high doses of glucocorticoids in the early posttransplantation period induced P-glycoprotein and
CYP which counterbalanced the inhibitory effects
of ciclosporin. Another observation is that oral prednisolone clearance was lower at 3–6 months than at
<1 month post transplantation,[90] which might be
explained by less P-glycoprotein or CYP induction
by the reduced glucocorticoid doses at 3–6 months.
A further study showed no differences between
prednisolone pharmacokinetics with and without
ciclosporin.[115] However, the latter study used intravenous prednisolone and therefore any effects of
ciclosporin on drug absorption could not be detected.
Clin Pharmacokinet 2005; 44 (1)
70
Czock et al.
Kidney transplant patients on ciclosporin had an
intravenous clearance of methylprednisolone that
was similar to the clearance in healthy volunteers
from the literature.[54] Sirolimus (rapamycin) reduced the oral clearance of prednisolone after prednisone and a negative correlation between sirolimus
AUC and prednisolone clearance was observed.[91]
Methylprednisolone affects ciclosporin pharmacokinetics. The clearance of intravenous ciclosporin
was increased after methylprednisolone pulse therapy (250 mg/day for 3 days),[116] which can be
explained by CYP induction. In contrast, another
study found higher ciclosporin plasma levels after
methylprednisolone (250–500 mg/day).[117] However, in the latter study a nonspecific RIA was used
and thus the contribution of ciclosporin metabolites
to the measured plasma levels is unclear. Ciclosporin pharmacokinetics were unaffected by
withdrawal of low-dose prednisolone for 24 hours in
liver transplant recipients.[118] However, enzyme induction, if present, would not be expected to resolve
within 24 hours.
Tacrolimus pharmacokinetics are similar to ciclosporin pharmacokinetics. Tacrolimus levels were
decreased in a liver transplant patient after methylprednisolone pulse therapy (625 mg/day for 3 days)
and recovered within 2 weeks.[110]
Sirolimus concentrations were not affected by
high doses of methylprednisolone.[119] Prednisone
dose reduction from 0.3 mg/kg to 0.12 mg/kg led to
1.6 times higher sirolimus concentrations in kidney
transplant recipients.[120]
1.4 Influence of Diseases on
Glucocorticoid Pharmacokinetics
Several diseases (e.g. renal failure, hepatic failure, severe obesity) have been reported to affect the
pharmacokinetics of glucocorticoids. In renal failure, prednisolone clearance was decreased and the
half-life was increased compared with healthy volunteers (table III).[10,33] A correlation between serum
creatinine and the prednisolone half-life has been
observed,[10] whereas the volume of distribution re 2005 Adis Data Information BV. All rights reserved.
mained unchanged.[10,33] The protein binding of
prednisolone decreased and thus the free fraction
increased in renal failure.[33] Methylprednisolone
pharmacokinetics were unchanged in patients with
renal failure. Only the conversion of the prodrug
methylprednisolone succinate to methylprednisolone was slower.[55] In contrast, dexamethasone
clearance was increased and its half-life decreased
in renal failure (table III).[10] This can be explained
by decreased protein binding of dexamethasone to
albumin in uraemia.[41] Similarly, the binding of
cortisol to albumin is reduced in uraemia,[23] whereas binding of cortisol to transcortin remains unchanged.[22] Cortisol metabolites accumulate in renal failure and are removed insufficiently during
haemodialysis.[79] The fraction of prednisolone removed during a 5-hour haemodialysis was
7–17.5%.[121] The fraction of methylprednisolone
removed during haemodialysis can be estimated to
be <10%.[122]
Chronic liver disease was associated with reduced clearance and higher plasma concentrations
of prednisolone in one study[83] but not in another.[10]
However, there was a trend to a prolonged half-life
in patients in the latter study. Methylprednisolone
pharmacokinetics were unchanged in patients with
chronic liver disease, with the exception of slower
conversion of the prodrug.[92] Dexamethasone clearance was decreased and the half-life was increased
in patients with chronic liver disease (table III).[10]
The half-life and protein binding of prednisolone
in obese individuals are similar to normal subjects,
but volume of distribution and clearance are increased. It has therefore been suggested that weightproportional dosage adjustments of prednisolone
should reflect total bodyweight.[56] In contrast, the
methylprednisolone half-life increased and clearance decreased in obese patients. The volume of
distribution was closely related to ideal bodyweight
(IBW), suggesting limited uptake of methylprednisolone into fat tissue. Thus, it was concluded that
methylprednisolone should be administered on the
basis of IBW.[25]
Clin Pharmacokinet 2005; 44 (1)
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
There are a number of reports for other diseases
that may affect glucocorticoid pharmacokinetics.
Patients with the nephrotic syndrome had decreased
total but normal unbound prednisolone concentrations.[123] Patients with inflammatory bowel disease
have variable absorption,[83,124] and fractional binding of prednisolone to plasma proteins was decreased in active disease.[125] Hyperthyroid patients
had decreased prednisolone concentrations.[83] Patients with cystic fibrosis had a higher volume of
distribution and normal half-life of oral prednisolone,[126] whereas prednisolone pharmacokinetics in
steroid-dependent asthmatics were unchanged compared with healthy individuals.[127] Children with
acute lymphoblastic leukaemia had a lower clearance and longer half-life.[128] Patients with acute
spinal cord injury had a lower systemic clearance of
methylprednisolone.[129]
2. Genomic and Nongenomic
Mechanisms of Glucocorticoid Effects
Glucocorticoids inhibit many events of the inflammatory and immune response by various mechanisms (table IV).[130,131] Most effects of glucocorticoids are mediated by glucocorticoid receptors, but
possibly not all. Basically, glucocorticoid mechanisms can be divided into genomic and nongenomic
mechanisms. Whereas the role of genomic mechanisms is well established, the importance of nongenomic mechanisms is still unclear.
2.1 Genomic Mechanisms
The genomic effects of glucocorticoids are characterised by a slow onset and slow dissipation of
the response, due to the time-consuming process of
mRNA transcription and translation (figure 1). The
start of mRNA induction for some proteins was seen
after 15 minutes in rat thymic lymphocytes.[132] Protein levels can be affected after 30 minutes and
effects on tissue or organ levels need hours to days.
It can be estimated that 100 to 1000 genes are up- or
down-regulated in a cell-type specific way.[133-135]
 2005 Adis Data Information BV. All rights reserved.
71
2.1.1 Glucocorticoid Receptors
The glucocorticoid receptor (GRα), a member of
a superfamily of ligand-regulated nuclear receptors,
consists of a ligand-binding domain, a DNA-binding
domain, and two activation-functional domains. The
inactive glucocorticoid receptor is retained in the
cytoplasm within a multiprotein complex containing
two heat shock protein molecules (HSP90). Additional molecules of this complex include the immunophyllins, HSP70, p23, and src.[136-138] The glucocorticoid receptor isoform GRβ, a splice variant,
does not bind glucocorticoids and its relevance in
glucocorticoid resistance is controversial.
Glucocorticoids bind to the ligand-binding domain of the glucocorticoid receptor GRα after entering the cell by passive diffusion through the cell
membrane. This binding leads to a conformational
change in the glucocorticoid receptor, which in turn
leads to dissociation of the multiprotein complex
(figure 1). The glucocorticoid receptor-glucocorticoid (GR/GC) complex is then localised to the nucleus via the nuclear pore complex. Dimerisation
with formation of glucocorticoid receptor homodimers is necessary for DNA interaction with glucocorticoid response elements (GREs) and subsequent
activation or repression of transcription (figure
1).[139,140] The transactivation potency of the GR/GC
complex is regulated intracellularly by coactivators
and corepressors,[141,142] and possibly by glucocorticoid receptor phosphorylation.[143,144] In addition,
monomeric glucocorticoid receptors inhibit the
proinflammatory transcription factors nuclear factor
κB (NF-κB) [figure 1] and activator protein 1 (AP1), independent of DNA binding. The importance of
the latter mechanism is underlined by the fact that
many inflammatory genes that are repressed by glucocorticoids do not contain a negative GRE.
2.1.2 Glucocorticoid Response Elements
The GREs in gene promoters are characterised by
the nonpalindromic consensus sequence 5′-XXTACAXXXTGTTCT-3′ containing two binding sites
for the glucocorticoid receptor homodimer. After
DNA association, the GR/GC homodimer (together
Clin Pharmacokinet 2005; 44 (1)
72
Czock et al.
Table IV. Molecular mechanisms of glucocorticoid effects
Mechanisms
Molecular effects
Cellular effects
Interactions of GR with GREs
Interactions of GR with transcription factors
(→ CBP → acetylation of core histones
→ increased gene transcription)
Anti-inflammatory/immunosuppressive effects
induction of anti-inflammatory cytokines
(e.g. IL-10, TGFβ)
induction of cytokine receptors
(e.g. IL-1RII, IL-10R, TGFβR)
induction of proapoptotic factors
Genomic mechanisms
Transcriptional
transactivation
Metabolic effects
induction of PEPCK, TAT (gluconeogenesis)
mobilisation of amino and fatty acids
Antiproliferative effects on non-immune cells
induction of p21CIP1 (e.g. renal mesangial cells)
induction of MKP-1 (e.g. osteoblasts)
Other effects
antiapoptotic effect (e.g. induction of c-IAP2)
up-regulation of β2-receptors
transrepression
Interactions of GR with nGREs
Interactions of GR with transcription factors
inhibition of AP-1, NF-κB
→ CBP associated HAT activity ↓
→ inhibition of histone acetylation
→ decreased gene transcription
Anti-inflammatory/immunosuppressive effects
suppression of:
cytokines (e.g. IL-1, IL-2, IL-6, IL-12, IFNγ)
chemokines (e.g. MCP-1, IL-8, eotaxin)
receptor expression (e.g. IL-2R)
adhesion molecules
direct (e.g. ICAM-1, E-selectin)
indirect via cytokine/chemokine suppression
(e.g. of IL-1β, TNFα)
inflammatory enzymes (e.g. COX-2, cPLA2, iNOS)
T cell proliferation (e.g. via IL-2↓)
Other effects
suppression of the hypothalamic-pituitary-adrenal axis
suppression of osteocalcin
suppression of matrix metalloproteinase
Post-transcriptional
Modification of mRNA stability
(shortening of the poly(A) tail)
Translational
Suppression of ribosomal proteins and
translation initiation factors
Post-translational
Protein processing, secretion
Suppression of COX-2, MCP-1, iNOS
Nongenomic mechanisms
Specific
classical GR
Cytosolic interactions (possibly via
components of the GR-multiprotein complex)
cPLA2 inhibition (via src/annexin-1)
Tertiary CAM structure (possibly via annexin-1)
nonclassical GR
Interaction with membrane GR
May induce apoptosis
Interaction with other receptors
May induce IP3, Ca2+, protein kinase C, cAMP, MAPK
Continued next page
 2005 Adis Data Information BV. All rights reserved.
Clin Pharmacokinet 2005; 44 (1)
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
73
Table IV. Contd
Mechanisms
Molecular effects
Cellular effects
Nonspecific
Glucocorticoid dissolves in membranes and may
alter
→ physicochemical membrane properties
(fluidity, ‘membrane stabilisation’)
→ activity of membrane associated proteins
AP-1 = activator protein 1; CAM = cellular adhesion molecule; cAMP = cyclic adenosine monophosphate; CBP = CREB binding protein; cIAP2 = cellular inhibitor of apoptosis; COX-2 = cyclo-oxygenase 2; cPLA2 = cytosolic phospholipase A2; GR = glucocorticoid receptor; GRE
= glucocorticoid response element; HAT = histone acetylase; ICAM = intercellular adhesion molecule; IFN = interferon; IL = interleukin;
iNOS = inducible nitric oxide synthase; IP3 = inositol-1,4,5-trisphosphate; MAPK = mitogen activated protein kinase; MCP-1 = monocyte
chemoattractant protein 1; MKP-1 = MAP kinase phosphatase 1; mRNA = messenger RNA; NF-κB = nuclear factor κB; nGRE = negative
GRE; PEPCK = phosphoenolpyruvate carboxykinase; TAT = tyrosine aminotransferase; TGFβ = transforming growth factor-β; TNF =
tumour necrosis factor.
with other cofactors) binds the transcriptional coactivator CREB binding protein (CBP)/p300 which in
turn binds the basal transcription factor apparatus
and starts gene transcription. DNA transcription,
once started, is independent of the further presence
of the GR/GC complex (‘hit and run’ principle).[145,146]
Acetylation and deacetylation of specific histone
residues regulates histone-chromatin interaction and
thus the accessibility of genes for transcription factors. CBP has intrinsic histone acetylase (HAT)
activity and thus can promote anti-inflammatory
gene transcription via histone acetylation and consecutive unfolding of the DNA.
2.1.3 Transcription Factors (Nuclear Factor κB and
Activator Protein 1)
The inflammatory response of tissue cells, stimulated, for example, by tumour necrosis factor
(TNFα) or interleukin (IL)-1β, is mediated intracellularly by the proinflammatory transcription factors
NF-κB (e.g. p65-p50 heterodimer) [figure 1] and
AP-1 (Fos-Jun heterodimer).[147,148] In later phases
of inflammation, NF-κB might also play a role in the
resolution of inflammation (e.g. via p50-p50
homodimers).[149]
Glucocorticoids reduce gene transcription by
interaction with the proinflammatory transcription
factors NF-κB and AP-1. Both factors and the
glucocorticoid receptor mutually repress each
other’s ability to activate transcription. Recruitment
of a histone deacetylase complex (HDAC) to the
 2005 Adis Data Information BV. All rights reserved.
proinflammatory p65-CBP HAT complex leads to
deacetylation of specific histone residues, DNA
folding, and thus to reduced transcription or silencing of proinflammatory genes.[150,151] Induction of
IκB or HDAC might play an additional role as a
long-term anti-inflammatory effect of glucocorticoids.[130,152]
2.1.4 Post-Transcriptional and
Translational Mechanisms
Protein synthesis depends on the stability and
half-life of mRNA, which is regulated by the length
of its poly(A) tail and other mechanisms.[130] Glucocorticoids can act by destabilising the mRNA of
proinflammatory proteins.[153,154] Additionally, glucocorticoids might act at the translational level by
suppression of ribosomal proteins and translation
initiation factors.
2.2 Nongenomic Mechanisms
Nongenomic mechanisms are characterised by a
rapid onset of effect (<15 minutes) because no time
is necessary for gene transcription and translation.
In addition, inhibitors of transcription do not modify
these effects in vitro. Data on nongenomic mechanisms are available mainly from animal cells using
gonadal steroids,[155,156] but glucocorticoids have also been studied.[136,157,158] Nongenomic mechanisms
can be classified into specific mechanisms where
glucocorticoids interact with a receptor, and nonspecific mechanisms where no receptor is involved.[159]
Clin Pharmacokinet 2005; 44 (1)
74
Czock et al.
Glucocorticoid
Cytokine receptor
Glucocorticoid receptor –
HSP90 complex
IκB
NF −κB
Specific nongenomic
effects
NF −κB
Anti-inflammatory genes
NF −κB
GRE
Proinflammatory
genes
Fig. 1. Genomic mechanisms of glucocorticoids in human cells. Mechanisms include transactivation via binding to a glucocorticoid response
element (GRE) in the promoter region of a gene (e.g. interleukin-10 gene) and transrepression via inhibition of the transcription factor NFκB. HSP90 = heat shock protein 90; IκB = inhibitor of NF-κB; NF = nuclear factor.
Nongenomic effects have been used to explain
the increased clinical effect of pulse therapy with
glucocorticoid doses >250mg. Genomic mechanisms are not sufficient to explain such effects, as it
has been estimated that all glucocorticoid receptors
are occupied after prednisolone 100–200mg.[157] Effects associated with nongenomic mechanisms can
lead to different in vitro drug potencies compared
with genomically mediated effects.[160,161]
 2005 Adis Data Information BV. All rights reserved.
2.2.1 Specific Nongenomic Mechanisms
Specific nongenomic mechanisms are mediated
via the classical glucocorticoid receptor (figure 1) or
nonclassical glucocorticoid receptors.[159] For example, a fast (<5 minutes) inhibitory effect of dexamethasone on cytosolic phospholipase A (cPLA)
activation in human pulmonary A549 cells has been
found to depend on the classical glucocorticoid receptor, but to be independent of transcription. This
effect was explained by dexamethasone-dependent
Clin Pharmacokinet 2005; 44 (1)
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
75
liberation of annexin 1 (formerly called lipocortin
1), which interferes with intracellular signal transduction and eventually inhibits cPLA activation.[136]
Experiments with cells from an annexin 1 knockout
mouse support these findings.[162]
2.2.2 Nonspecific Nongenomic Mechanisms
Nonspecific nongenomic mechanisms are due to
direct interaction of glucocorticoids with cell membranes. It has been suggested that the lipophilic
steroids physically dissolve into lipid membranes
and modify physicochemical membrane properties,
which in turn affect the activity of membrane-associated proteins.[163,164] Suppression of cellular energy metabolism leading to reduced cell function
could be a consequence.[157] Stabilisation of
lysosomal membranes might be another mechanism
(figure 2).[165]
3. The Host Defence Response and the
Effects of Glucocorticoids
In order to understand the multiple effects of
glucocorticoids, a review of the host defence response is needed. The host defence response includes
inflammation, the immune response, coagulation,
tissue repair and activation of the hypothalamicpituitary-adrenal axis.
3.1 Molecular Mechanisms
On the molecular level, inflammation and the
immune response are mediated by cytokines (e.g.
Glucocorticoid
?
Basement
membrane
?
Cell membrane
Lysosome
Fig. 2. Nonspecific nongenomic mechanisms of glucocorticoids. These might affect membranes by physicochemical mechanisms. Involved
membranes include cell membranes, lysosomal membranes and possibly basement membranes.
 2005 Adis Data Information BV. All rights reserved.
Clin Pharmacokinet 2005; 44 (1)
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Czock et al.
IL-1 to IL-6, IL-11 to IL-13, TNFα, interferon
[IFN]γ, macrophage migration inhibitory factor
[MIF]), chemokines (e.g. IL-8, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]1α, regulated upon activation normal T cell expressed and secreted [RANTES],
eotaxin), kinins and kinin receptors, adhesion molecules, and inflammatory enzymes (e.g. inducible
nitric oxide synthase [iNOS], cyclo-oxygenase
[COX]-2).
3.1.1 Cytokines and Chemokines
Cytokines, extracellular signalling proteins that
induce cellular responses, affect protein production,
antigen expression and proliferation. Glucocorticoids act by suppression of proinflammatory cytokines (e.g. IL-1β, IFNα), induction of decoy receptors that trap proinflammatory cytokines (e.g.
IL-1RII), induction of anti-inflammatory cytokines
(e.g. transforming growth factor [TGF]-β, IL-10),
and induction of anti-inflammatory cytokine receptors (e.g. TGFβR, IL-10R).[135,166]
Chemokines, extracellular signalling proteins
that affect cellular migration, can be suppressed
(e.g. MCP-1 = CCL2, IL-8 = CXCL8, MIP-1β =
CCL4, eotaxin = CCL11) or induced (e.g. interferon-inducible protein IP-10 = CXCL10,
fractalkine = CX3CL1) by glucocorticoids.
3.1.2 Inflammatory Enzymes
Arachidonic acid, an important mediator of the
inflammatory response, is produced by phospholipase A2 (PLA2). Arachidonic acid is metabolised
by COX, by thromboxane synthase, and by lipoxygenase, but arachidonic acid may also have direct
effects itself as a second messenger.[167] COX-2, the
inducible COX, is induced by inflammatory and
mitogenic stimuli.
Glucocorticoids suppress cytosolic cPLA2 and
COX-2 expression via genomic mechanisms.[168]
Additionally, a specific nongenomic mechanism has
been suggested for suppression of cPLA2 activity.[136] As a consequence, the production of
arachidonic acid and its metabolites is decreased.
 2005 Adis Data Information BV. All rights reserved.
iNOS, which generates nitric oxide, is involved
in vasodilatation at the site of inflammation. Glucocorticoids can suppress iNOS expression by transcriptional and post-transcriptional mechanisms as
shown in vitro.[169,170] Glucocorticoid treatment reduced nitric oxide levels in exhaled air in patients
with pulmonary sarcoidosis or cystic fibrosis.[171,172]
3.2 Cellular Mechanisms
3.2.1 Cell Trafficking and Adhesion Molecules
The inflammatory process depends on migration
of inflammatory and anti-inflammatory immune
cells to the site of inflammation (cell trafficking).
Activation of immune cells is mediated by
chemokines (e.g. MCP-1, IL-8). Exit of immune
cells from the blood vessels is mediated by cellular
adhesion molecules (CAMs).[173]
Glucocorticoids can reduce the recruitment of
immune cells to the site of inflammation by repression of adhesion molecules, either directly as shown
in vitro[174,175] or indirectly via suppression of proinflammatory cytokines and transcription factors. In
addition, glucocorticoids can induce rapid changes
in the surface distribution of CAMs, possibly by a
nongenomic mechanism.[173,176] Glucocorticoid-induced granulocytosis can be explained by limited
neutrophil emigration from the blood and neutrophil
mobilisation from the bone marrow.
3.2.2 T Cell Differentiation
T Cell subsets include CD4+ helper (Th) cells,
CD8+ cytotoxic T (Tc) cells, CD4+CD25+ natural
regulatory T (Tr) cells and adaptive/inducible regulatory T (Treg1) cells[177,178] and CD8+CD28- suppressor T cells.[179] Naive T helper (Th0) cells differentiate to Th1 or Th2 cells depending on the stimulus.[180] Regulatory T cells suppress immune
responsiveness and induce tolerance.[181] Natural Tr
cells express membrane-bound TGFβ that can deliver signals to target cells via a contact-dependent
process.[182] Adaptive Treg1 cells produce IL-10 and
TGFβ.[178]
Clin Pharmacokinet 2005; 44 (1)
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
Glucocorticoids inhibit the costimulatory CD40ligand on lymphocytes[135] and costimulatory molecules on dendritic cells (e.g. CD40, CD86).[183]
Eventually, dendritic cells are switched to produce
IL-10 instead of IL-12,[184] which in turn limits
differentiation of Th0 to Th1 cells. In addition,
glucocorticoids might induce differentiation of Th0
to Treg1 cells.[185,186] Up-regulation of TGFβ receptors on lymphocytes might enhance the action of
regulatory T cells.
3.2.3 Cell Proliferation
Glucocorticoids affect the proliferation of
immune and nonimmune cells. Indirect glucocorticoid effects include inhibition of T cell growth factor production (e.g. IL-2), which leads to reduced T
cell proliferation. Direct glucocorticoid effects include transcription of the protein p21CIP1, an inhibitor of cyclin-dependent kinase, which leads to cell
cycle arrest as shown in renal mesangial cells.[187]
Importantly, glucocorticoids have to be studied over
a wide concentration range. Low to medium concentrations of prednisolone (10–9 to 10–6 mol/L) stimulated intestinal epithelial cell proliferation, whereas
very high concentrations (10–4 mol/L) inhibited intestinal epithelial cell proliferation.[188]
3.2.4 Apoptosis
Glucocorticoids have apoptotic or antiapoptotic
effects, depending on the cell type. Apoptosis of
immune cells (e.g. lymphocytes) leads to attenuation of the inflammatory and immune response,
whereas antiapoptotic effects could protect resident
cells (e.g. epithelial cells) of the inflamed tissue.[189]
Apoptosis of T cells could be an important mechanism of intravenous glucocorticoid pulse therapy.
Administration of methylprednisolone 500–1000mg
induced apoptosis of T helper cells in patients with
autoimmune diseases.[190,191] The degree of T cell
apoptosis was dependent on the glucocorticoid dose
in an animal model.[192]
Glucocorticoids increase the rate of apoptosis in
eosinophilic granulocytes in vitro, which could be
important in the treatment of asthma, where eosino 2005 Adis Data Information BV. All rights reserved.
77
philic inflammation prevails. In contrast, glucocorticoids decrease the rate of apoptosis in neutrophilic
granulocytes, which could explain the limited clinical efficacy of long-term glucocorticoid treatment
in chronic obstructive pulmonary disease, where
neutrophilic inflammation prevails.[193,194]
Glucocorticoids can induce apoptosis by several
mechanisms. Firstly, cytokines that represent survival factors for immune cells are down-regulated by
glucocorticoids, which can lead indirectly to
apoptosis. Secondly, glucocorticoids might induce
proapoptotic factors. Thirdly, glucocorticoids might
inhibit NF-κB mediated antiapoptotic mechanisms.[195]
Antiapoptotic mechanisms of glucocorticoids include induction of receptors for antiapoptotic signals[196] and induction of intracellular antiapoptotic
factors (e.g. the cellular inhibitor of apoptosis cIAP2).[197]
3.2.5 Basement Membranes
The renal glomerulus normally produces a protein-free filtrate, but in the nephrotic syndrome the
permeability of the glomerular capillary wall for
macromolecules is increased. Glucocorticoids decrease proteoglycan synthesis in glomerular epithelial and mesangial cells by genomic mechanisms.[198,199] Glucocorticoids inhibit the release of
matrix metalloproteinases, as shown in alveolar
macrophages.[200] In addition, nonspecific glucocorticoid effects on basement membranes might be
assumed.
3.3 Inflammation
Acute inflammation is characterised by four consecutive phases. These are exudation, local infiltration by neutrophils, apoptosis of neutrophils, and
local infiltration of mononuclear cells. Exudation is
due to increased vascular permeability of capillaries
and venules. Vasoactive factors (e.g. nitric oxide,
prostacyclin) and reduced adrenergic receptor activity lead to dilatation of arterioles producing local
erythema and heat. Infiltration by neutrophils is
Clin Pharmacokinet 2005; 44 (1)
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Czock et al.
mediated by adhesion molecules and chemokines.
Apoptosis and phagocytosis of neutrophils by
mononuclear cells is important for the resolution of
inflammation, which is coordinated by anti-inflammatory mediators derived from arachidonic acid
(e.g. lipoxins and cyclopentane prostaglandins
[cyPGs]) and by anti-inflammatory cytokines (e.g.
IL-10, TGFβ).[149]
Glucocorticoids counteract the acute inflammatory effects on the microcirculation resulting in
vasoconstriction, reduction of oedema and a decreased rate of leucocyte migration.[201] In addition,
glucocorticoids could affect the resolution of inflammation by inducing annexin-1 derived peptides
that act at the lipoxin A4 receptor.[202] Glucocorticoid treatment increases IL-10,[203] which inhibits
NF-κB activity and affects many immune cells.[204]
3.4 Immune Response
The following events are involved in the immune
response: (i) antigen processing/presentation and activation of macrophages/dendritic cells; (ii) antigen
recognition and activation of T cells; (iii) generation
of T helper cell response; (iv) production of proinflammatory cytokines; (v) adhesion and migration;
(vi) inflammation and cell injury; and (vii) repair
and restitution. All of these events can be affected
by glucocorticoids.
In acute kidney transplant rejection T helper cells
react in a Th1 type immune response[205] after recognition of donor antigen.[206] Glucocorticoids act on
various levels of transplant rejection. They inhibit
the differentiation and antigen presentation of
macrophages and dendritic cells[184,207] and thus suppress the initiation of an immune response. Glucocorticoids inhibit proinflammatory cytokine production of IL-1, IL-2, IL-6, IL-12, IFNγ and TNFα in
various cells,[208] leading to suppression of activated
T cells. In addition, apoptosis of T cells is induced
by glucocorticoid pulse therapy,[190,191] which could
also be important in the treatment of acute transplant
rejection. Furthermore, down-regulation of adhesion
molecules and chemokine receptors that are up 2005 Adis Data Information BV. All rights reserved.
regulated in acute rejection[205,209] could play a role.
Finally, inhibition of the effector mechanisms of
transplant destruction might be involved in glucocorticoid efficacy.
4. Adverse Effects of Glucocorticoids
It is a general observation that adverse effects of
glucocorticoid treatment appear more likely after
long-term treatment but less frequently after shortterm treatment, even with high glucocorticoid
doses.[210] This observation is compatible with timedependent genomic effects that do not increase further after high doses when glucocorticoid receptor
saturation is already achieved.
Glucocorticoids induce or aggravate diabetes
mellitus and induce arterial hypertension.[211-213]
Glucocorticoids negatively regulate the hypothalamic-pituitary-adrenal (HPA) axis and rapidly inhibit
adrenal secretion of cortisol. Long-term inhibition
can lead to adrenal atrophy.[214] Unfortunately adrenal suppression cannot be predicted from the dose or
duration of glucocorticoid therapy.[215] One of the
most serious adverse effects of glucocorticoid therapy is the increased risk of infection.[216,217] The risk
increases with the dose and duration of glucocorticoid treatment.
Long-term treatment with glucocorticoids causes
osteoporosis by various mechanisms affecting osteoblastic and osteoclastic functions.[211,218,219] Clinically, the fracture risk increases with the glucocorticoid dose[220] and correlates better with the daily
dose compared with the cumulative dose.[221] Skin
atrophy is due to suppression of cutaneous cell proliferation and protein synthesis (e.g. collagen) by
glucocorticoids. Skin thinning begins after glucocorticoid treatment for only a few days.[211]
Other adverse effects associated with glucocorticoid therapy include gastrointestinal ulcers (controversial),[211,222,223] cataract formation,[224] redistribution of body fat, dyslipidaemia, myopathy, bone
necrosis,[225] growth retardation in children,[226]
glaucoma, psychosis, increased appetite and, rarely,
Clin Pharmacokinet 2005; 44 (1)
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
allergic reactions.[227] Increased appetite can also be
a desired effect, e.g. in cancer patients.[228]
5. Pharmacodynamics
of Glucocorticoids
The pharmacodynamic properties of a drug are
the mathematical description for the quantitative
relationships between drug concentration and effects.
5.1 Biomarker and Surrogate Endpoints
Many studies have analysed the pharmacodynamics of glucocorticoids, but the results vary
depending on the biomarker used. There are many
biomarkers, but only a few well-evaluated surrogate
endpoints (e.g. HbA1c for complications of diabetes
mellitus, bone mineral density for fracture risk in
osteoporosis).
At the molecular level, endogenous cortisol is
used as a biomarker for HPA suppression.[30] Osteocalcin, secreted by osteoblastic cells during osteogenesis, is used as a biomarker for glucocorticoid
effects on bone formation.[57,229] Molecular markers
used in vitro to evaluate glucocorticoid potencies
include transcription factors (e.g. AP-1, NF-κB),
mRNA levels and gene expression (e.g. cytokines or
membrane proteins).[230-234]
At the cellular level, the number of T cells is a
frequently used biomarker in vivo because T cells
play a central role in the immune response.[30,31,58-60]
The suppression of CD4+ (T helper) cells by glucocorticoids might be a surrogate endpoint for the
prevention and treatment of transplant rejection and
the therapy of autoimmune diseases. On the other
hand, low CD4 counts in long-term immunosuppression were correlated with an increased frequency of infections,[235] neoplasms[236,237] and atherosclerosis.[238] The number of circulating blood cells
reflects migration between the intravascular and extravascular compartments,[31] but apoptosis might
play an additional role after very high glucocorticoid
doses.[190,191] Lymphocyte activation and proliferation are used as a biomarker in vitro.[61,239,240]
 2005 Adis Data Information BV. All rights reserved.
79
At the tissue/organ level, topical skin blanching
as a result of vasoconstriction of the skin microvasculature has been used as a biomarker for dermatological glucocorticoid products.[241,242]
5.2 Potency
The effect (E), as measured by a change of a
biomarker, depends on drug concentration (C). The
basic correlation between effect and concentration is
described by the sigmoid Emax model, where Emax is
the maximum achievable effect (capacity parameter) and CE50 is the concentration producing the
half-maximal effect (sensitivity parameter). The latter has also been named EC50, CI50, or IC50, depending on circumstances. The sigmoidicity constant H
determines the slope of the curve (equation 1).
E = E max ·
CH
CE
H
50
+CH
(Eq. 1)
The parameter CE50 is a hybrid of receptor affinity, the number of receptors, and subsequent effector
mechanisms. The potency of a drug is calculated as
the inverse of CE50, since a high potency indicates
that only a low concentration is needed to produce
the half-maximal effect (equation 2).
Potency =
1
CE 50
(Eq. 2)
The relationship between drug concentrations
and effects can be determined in vitro where constant concentrations and a defined exposure time are
used. Eventually an in vitro CE50 is calculated. In
vivo, drug concentrations are constantly changing
and the different half-lives of glucocorticoids influence the duration of effect and obscure drug potency.[243] The influence of both factors (CE50 and drug
half-life) on the effect can be distinguished by pharmacokinetic/pharmacodynamic analysis and an estimation of in vivo CE50. Importantly, when in vitro
and in vivo CE50s are compared, protein binding has
to be considered. Such a comparison is further complicated because local (biophase) concentrations
Clin Pharmacokinet 2005; 44 (1)
80
have to be used depending on the selected biomarker. These local concentrations are determined by
drug distribution and local glucocorticoid metabolism.
The potency of a given glucocorticoid differs
depending on biomarker and cell type, despite the
glucocorticoid receptor being the same in different
cells and tissues. Potency differences between biomarkers are explained by diverse effector mechanisms. Potency differences between cell types might
be explained by a different number of glucocorticoid
receptors per cell, by a different glucocorticoid
binding affinity due to the phosphorylation status of
the glucocorticoid receptor,[143,144] possibly by glucocorticoid receptor diversity,[244] by intracellular
modulation of the transactivation potency of the GR/
GC complex by coactivators and corepressors, by a
different histone deacetylase activity,[245] and possibly also by differences in nongenomic mechanisms
between cell types.
The potency for a given effect differs between the
various glucocorticoids. This potency has been correlated with glucocorticoid affinity for the glucocorticoid receptor.[3,36,234,246] For example, there was a
good correlation between the relative glucocorticoid
receptor affinity of various glucocorticoids and the
inhibition of whole-blood lymphocyte proliferation.[247] How different glucocorticoid receptor affinities translate to different effects is not entirely
clear. There is evidence that the molecular structure
of different glucocorticoids does not influence the
DNA binding affinity of the glucocorticoid receptor,
but has allosteric effects on glucocorticoid receptorDNA dissociation.[146]
The ranking of glucocorticoid potencies depends
on the experimental design. Experiments looking at
genomic effects can lead to other rankings of
glucocorticoid potency compared with nongenomic
effects. For example, using cPLA2 activation as a
biomarker, dexamethasone had a lower CE50 (2 ×
10–8 mol/L), and thus higher potency compared with
hydrocortisone (CE50 7.5 × 10–8 mol/L) in A549
cells (a human lung adenocarcinoma cell line). In
 2005 Adis Data Information BV. All rights reserved.
Czock et al.
contrast, using COX-2 expression as a biomarker,
hydrocortisone had a lower CE50 (7.5 × 10–8 mol/L)
compared with dexamethasone (1 × 10–7 mol/L).
Furthermore, prednisolone inhibited COX-2 expression and not cPLA2 activity, but methylprednisolone
inhibited cPLA2 activity and not COX-2 expression.[160] These results can be explained only by
distinct cellular pathways (i.e. nongenomic mechanisms in the case of cPLA2 inhibition). Another study
analysed COX-2 expression and activity in human
monocytes and found a low CE50 for dexamethasone, a medium CE50 for methylprednisolone, and
a high CE50 for hydrocortisone, in agreement with
receptor binding affinities.[232] These contradictory
results could be due to the cell type studied (immune
cell vs lung cell), but can also be explained by the
design of the experiments. Croxtall et al.[160] used an
incubation period of 3 hours, whereas Santini and
colleagues[232] used a 24-hour period. The short incubation period of 3 hours is thought to favour
nongenomic effects, whereas an incubation period
of 24 hours would favour genomic effects.
Nongenomic effects of glucocorticoids on cellular energy mechanisms have been suggested.[157]
Cellular oxygen consumption is a biomarker for
leucocyte activation, as immune functions require
energy. Oxygen consumption by peripheral blood
mononuclear cells was increased in patients with
rheumatic disease and normalised after glucocorticoid treatment.[248] Using cellular energy consumption as a biomarker, the following relationship was
found in vitro: dexamethasone (1.2) > methylprednisolone (1.0) > prednisolone (0.4) [relative
drug potencies compared with methylprednisolone].[161]
5.3 Clinical Efficacy
Clinical efficacy depends on pharmacodynamic
(e.g. potency) and pharmacokinetic (e.g. duration of
the drug at the receptor site) characteristics of a
drug. Taken together, both parameters determine the
duration of the momentary effect, which in turn
correlates with overall clinical efficacy:
Clin Pharmacokinet 2005; 44 (1)
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
potency + presence at the receptor site
→ momentary effect course (effect duration)
sum of momentary effects → clinical efficacy
Mathematically, pharmacokinetic/pharmacodynamic models describe the momentary effect course.
This effect course is characterised by the duration of
effect (i.e. the time until the effect drops below a
specified value). The momentary effect course can
be summed up as the area under the effect-time
curve (AUETC or AUEC) or as the area between the
baseline and effect curve (ABEC), which are assumed to correlate with the clinical effect.[249]
5.4 Pharmacodynamic
Drug-Drug Interactions
Drug-drug interactions can occur on a pharmacodynamic level when the same effector pathways are involved. For example, synergistic effects
of prednisolone, ciclosporin and sirolimus on lymphocyte proliferation have been demonstrated in
vitro.[250] Recombinant human IL-10 and prednisolone additively inhibit lymphocyte proliferation in
vitro.[239] In vivo, IL-10 increases prednisolone-induced lymphocyte suppression and neutrophil stimulation, but decreases prednisolone-induced monocyte suppression. These changes were due to altered
glucocorticoid potency whereas pharmacokinetics
were unchanged.[62]
Theophylline has a glucocorticoid-sparing effect
in patients with asthma,[251] which can be explained
on a molecular level by enhanced HDAC activity in
epithelial cells and macrophages.[252] In contrast to
theophylline, smoking reduces HDAC activity,
which might explain the enhanced expression of
inflammatory mediators in smokers.[253] Clarithromycin increases the glucocorticoid sensitivity of
lymphocytes from patients with asthma as measured
by suppression of lymphocyte activation in vitro.[254]
Glucocorticoids and β2-agonists act synergistically
on bronchial smooth muscle cell proliferation as
shown in vitro.[255]
 2005 Adis Data Information BV. All rights reserved.
81
6. Pharmacokinetic/
Pharmacodynamic Models
Generally, mathematical models can be put into
two categories: (i) models of data, also called empirical or descriptive models; and (ii) models of system, also called mechanistic or explanatory models.[256,257] For predictions, usually a mechanistic
model and a critical evaluation of the model is
required. Predictions can include the pharmacodynamic response to altered dosage regimens (i.e.
dose, timing, route of administration),[63,258,259] the
pharmacodynamic response to altered pharmacokinetics (e.g. elimination conditions), or prediction
of clinical pharmacodynamics based on in vitro
data.[3,5]
The pharmacokinetic part of the pharmacokinetic/pharmacodynamic model depends on the pharmacokinetics of the administered drug. Free drug
concentrations should be measured if the pharmacokinetics of total drug concentrations are nonlinear or
if inclusion of constants from in vitro measurements
in the pharmacodynamic model is desired. The pharmacodynamic part of the pharmacokinetic/pharmacodynamic model depends on the selected biomarker. In the case of receptor-mediated effects,
the Emax and the sigmoid Emax models are the most
widely used.[4] Generally, the simplest model, which
explains observations satisfactorily and makes correct predictions of future experiments, is regarded as
an appropriate model. Therefore the sigmoid Emax
model (using three model parameters) should only
be chosen if the simple Emax model (using two
model parameters) is not sufficient. Pharmacokinetic/pharmacodynamic models including clinical
endpoints (e.g. transplant rejection, response rate,
disease progression[260]) have not been published yet
for glucocorticoids.
A lag between the time of maximum effect and
the time of maximum concentration may be explained by the link in the pharmacokinetic and pharmacodynamic model. Firstly, a hypothetical effect
compartment can be presumed (biophase distribution model).[1,4] However, it has been argued that
Clin Pharmacokinet 2005; 44 (1)
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Czock et al.
this approach is only valid if the lag time is due to
protracted drug delivery to the biophase. Secondly,
an indirect response model should be used if the
mechanism is, for example, inhibition of the production of a biomarker, such that the observed decrease
in this biomarker depends on time-limited elimination through other mechanisms.[1,261] Both models
(effect compartment vs indirect response model) can
mimic each other under certain circumstances,[262]
but model selection based on mechanistic knowledge of the drug action should provide a more
reliable model.[263] Thirdly, a transduction model
should be used if time-dependent transduction processes are involved.[1,61,264] A fourth option is to
include a lag time.[3,64,65] The latter option lacks a
physiological basis, but satisfactory predictions
have also been possible with such a model.[3,65]
6.1 Pharmacokinetic/Pharmacodynamic
Analysis of Glucocorticoids
Effect compartment models have been used for
the description of lymphocyte suppression by
glucocorticoids, which is maximal 4–6 hours after
the maximum glucocorticoid concentration is
reached.[60,66,67] However, it is unlikely that drug
distribution to the biophase is the physiological
mechanism that explains the delay of the glucocorticoid effect on lymphocytes. Therefore, using lymphocyte suppression as a biomarker, the effect compartment model would be classified as a descriptive
model. Notably, the estimated CE50 values varied
depending on the applied dose level,[60,67] which
indicates selection of the wrong model because
CE50, as a parameter of the drug, should be independent of the dosage scheme. However, another explanation could be the measurement of total and not
free plasma concentrations of prednisolone in these
studies.
Indirect response models have been used for
glucocorticoid effects on blood cell count and endogenous cortisol. In these models, cell migration or
secretion of cortisol into the blood is blocked by
glucocorticoids. Elimination of pre-existing blood
 2005 Adis Data Information BV. All rights reserved.
pools by physiological mechanisms needs some
time, and the effect delay is thus explained by a
physiological mechanism.[30,31,58,61,84] A comparison
between an indirect response model (formerly
named direct suppression model) and an effect compartment model (using the Emax model, the sigmoid
Emax model or a threshold Emax model) for glucocorticoid effects (biomarker: basophil count) revealed that the indirect response model provided
more consistent results.[6]
Inclusion of a baseline function into the model is
necessary for biomarkers that display a circadian
pattern (e.g. endogenous cortisol, blood lymphocytes, osteocalcin[265]). A number of methods to
account for baseline variation of endogenous cortisol have been compared recently and the method
using Fourier analysis proved to be the best.[266]
Simpler and more often used methods are the use of
sinus functions[24,30,61] and the use of a linear release
model.[267,268] When baseline variation is disregarded, the effect might be overestimated and the concentration CE50 would be lower compared with a
model where a baseline function is included (e.g.
CE50 = 1.5 µg/L[64] vs 20.12 µg/L[68] for T helper
cell suppression by methylprednisolone). Advanced
models can also explain the circadian pattern of
lymphocytes by the circadian pattern of cortisol
secretion.[31,59]
Sophisticated mechanistic models including molecular aspects like glucocorticoid receptor downregulation have been developed and evaluated in
animal models.[133,269]
6.2 In Vivo Potency
We have summarised the in vivo CE50 values of
selected glucocorticoids in table V. In order to compare different glucocorticoids, a potency ratio can be
calculated from their CE50 values for a given biomarker. For example, a potency ratio of 17.1 was
found for T helper cell suppression by methylprednisolone compared with cortisol.[31] Comparing
the CE50 values for various biomarkers of estimated
free methylprednisolone and free prednisolone
Clin Pharmacokinet 2005; 44 (1)
Drug
Cortisol/
Drug plasma
Cellular effects
concentration
measured
lymphocyte T helper cell
suppression suppression
cytotoxic T
cella
suppression
Total
6.7 ± 4.9b
103.0 ± 17.5
hydrocortisone
179.0 ± 66.2
cortisol
glucose
suppression induction
osteocalcin water
suppression retention
4.6 ± 5.3
15.4 ± 3.4
Total
Free
Methylprednisolone
monocyte neutrophil
suppression induction
(56.4–79.3)
Free
Prednisolone
67.9 ± 20.7
Adverse effects
basophil
suppression
Totalc
125.3 ± 65.2
61.9 ± 40.6
9.7 ± 3.4
(90.4–173.9)
(48.8–75.0)
(9.0–10.3)
9.7 ± 7.8
5.8 ± 6.7
12.1 ± 8.1
5.7 ± 6.4
10.5 ± 6.1 29.2 ± 31.5
0.9 ± 1.3
(4.7–15.1)
(3.2–15.1)
(4.8–19.2)
(15.0–57.7)
(0.3–1.9)
10.5 ±
11.8 ± 11.5d
51.0 ± 43.3
7.2 ± 6.1
22.4 ± 27.5
1.0 ± 1.1
13.9
(1.4–22.8)
(18.5–112.0)
(2.1–14.3)
(8.4–36.0)
(0.1–2.9)
4.0 ± 4.7
18.0 ± 4.7
3.7 ± 5.3
0.1 ± 0.07
4.5
102.7
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
 2005 Adis Data Information BV. All rights reserved.
Table V. Glucocorticoid pharmacodynamics. The concentrations producing the half-maximum effect CE50 (µg/L) of selected glucocorticoid effects are shown. The pooled mean ±
pooled standard deviation (see Appendix) and the range of the primary mean values (minimum–maximum) are given for cases where more than one study was
found[3,6,24,25,28-31,36,40,43,55,57-59,61-68]
8.8
(6.0–13.9)
Dexamethasone
Totalc
2.9 ± 1.0
(0.9–6.0)
26.9
(2.2–6.1)
These CD3+/CD8+ cells were named T suppressor cells in other studies.
b
This very low value is most probably due to the lack of a baseline function in the original model.[66]
c
When free concentrations were given, these were converted to total concentrations using the free fraction given in the respective study.
d
One study used the sigmoid Emax model and estimated the sigmoidicity parameter H as 1.2 ± 0.1.[64]
Emax = maximal effect; Free = unbound to plasma components; Total = plasma bound and free.
83
Clin Pharmacokinet 2005; 44 (1)
a
84
Czock et al.
(table V), we find potency ratios between 1 and 6. In
accordance with these ratios, a retrospective study
of kidney transplant patients suggested that methylprednisolone might be superior to prednisolone for
maintenance immunosuppression.[270]
6.3 Selected Examples
6.3.1 Influence of Sex on Glucocorticoid
Pharmacokinetic/Pharmacodynamic Properties
Pharmacokinetic differences between males and
females have been reported for prednisolone and
methylprednisolone. The prednisolone clearance is
lower[84] but methylprednisolone clearance is
higher[68] in females compared with males. However, based on pharmacodynamic measurements, it
was concluded that dose adjustment is not necessary.[68,84] For example, the higher clearance of
methylprednisolone in women was compensated by
a higher potency (i.e. a lower CE50), leading to the
same overall effect.[68] The conclusions from these
studies are limited to the biomarkers employed, but
they underline the importance of performing pharmacodynamic analyses.
6.3.2 Influence of Age on Glucocorticoid
Pharmacokinetic/Pharmacodynamic Properties
The frequency and severity of adverse events
may be increased in elderly patients. Baseline cortisol is similar in young and elderly males, but
adrenal suppression (biomarker: endogenous cortisol) after administration of methylprednisolone
was greater in the elderly.[271] This can be explained
by a decrease in methylprednisolone clearance to
66% and an increase in the half-life to 130% in the
elderly (69–82 years) males.[69] Also prednisolone
clearance was lower (62%) in elderly subjects
(65–89 years).[272] However, in the latter study adrenal suppression (biomarker: endogenous cortisol)
after administration of prednisolone was lower in
the elderly.
 2005 Adis Data Information BV. All rights reserved.
6.3.3 Once- Versus Twice-Daily
Glucocorticoid Administration
Due to their short elimination half-lives, prednisolone and methylprednisolone concentrations fall to
below their CE50 values (biomarker: T helper cells)
within 12 hours after administration (low dose).
Eventually the number of T helper cells increases
again and also shows a small rebound. This rebound
can be explained by ongoing suppression of endogenous cortisol (the CE50 for cortisol suppression is
lower than the CE50 for T helper cell suppression),
which in turn leads to further diminished T helper
cell suppression.
As T helper cells play a central role in transplant
rejection, it has been suggested that the efficacy of
glucocorticoids might be increased by twice-daily
compared with the traditional once-daily administration.[64,67] Thus, glucocorticoid efficacy would be
greater, which might allow a lower total daily
dose.[63] Theoretically, adverse effects with CE50
values higher or equal compared to the peak concentration should be reduced in parallel with the total
daily dose.
In order to compare once-daily with twice-daily
administration we performed a simulation with
methylprednisolone 8mg once-daily versus 4mg
twice-daily. We used an established model and published parameter values for methylprednisolone effects on T helper cells and endogenous cortisol.[30,273] The pharmacokinetic part of the model
was a one-compartment model and the pharmacodynamic part was a precursor-dependent indirect response model (see Appendix). Simulations were
done with the use of the software WinNonlin Professional 4.0.1 (Pharsight Corporation, California).
The total effect correlates with the area between the
baseline curve without drug administration and the
effect curve after drug administration. This simulation showed that twice-daily administration has a
greater total effect despite the same total dose (figure 3). The total effect of methylprednisolone on T
helper cells is stronger and the rebound of T helper
cells is lower after twice daily administration. Thus,
a lower total dose might be possible. However,
Clin Pharmacokinet 2005; 44 (1)
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
85
T helper cells without methyprednisolone
administration (baseline curve)
Methylprednisolone 8mg once daily
Methylprednisolone 4mg twice daily
150
750
100
500
50
250
0
8:00
16:00
0:00
0
8:00
Time (h)
Fig. 3. Effect of methylprednisolone on T helper cells after 8mg
once or 4mg twice daily administration. Methylprednisolone concentrations (lower two curves) and effect on T helper cell counts
(upper three curves) after methylprednisolone were simulated using
an established model and published parameter values (see Appendix).[30]
adverse effects with low CE50 values, such as suppression of endogenous cortisol, might also be
greater (figure 4). This simulation is in agreement
with measured concentrations and effects after fractionated dose administration. Administration of
twice-daily dose fractions increased the immunosuppressive efficacy of methylprednisolone (biomarker: T helper cell suppression) while it did not
increase short-term adverse effects (biomarker: insulin and glucose), except for endogenous cortisol.[64]
6.3.4 Adverse Effects
The CE50 for glucose induction is higher than the
CE50 for lymphocyte suppression.[3,65] Thus, if a
smaller daily dose is possible, e.g. with administration of twice-daily doses, the overall effect of glucocorticoids on glucose metabolism should be less.
The degree and duration of endogenous cortisol
suppression is dose dependent.[7] However, it is unclear whether the degree of short-term cortisol suppression correlates with adrenal atrophy and limited
adrenal reserve or not.[215]
 2005 Adis Data Information BV. All rights reserved.
Clinically, glucocorticoid dosage practice can be
divided into five categories. These are low dose
(≤7.5mg prednisolone equivalent per day), medium
dose (>7.5mg, but ≤30mg prednisolone equivalent
per day), high dose (>30mg, but ≤100mg prednisolone equivalent per day), very high dose (>100mg
prednisolone equivalent per day), and pulse therapy
(≥250mg prednisolone equivalent per day for one or
a few days). The first three categories were estimated to correspond to <50%, 50–100%, and 100%
glucocorticoid receptor saturation. The latter two
categories are assumed to enhance clinical effects by
additional nongenomic mechanisms.[274]
7.1 Glucocorticoid Pulse Therapy
It is usual practice to give very high glucocorticoid doses if a rapid effect is needed in emergency
situations. After induction of a clinical response,
glucocorticoids are administered in lower doses to
maintain this effect. It has been speculated that the
induction of immunosuppression reflects other pharEndogenous cortisol without methylprednisolone
administration (baseline curve)
Methylprednisolone 8mg once daily
Methylprednisolone 4mg twice daily
200
Endogenous cortisol (µg/L)
1000
Methylprednisolone (µg/L)
200
1250
T helper cells (cells/µL)
7. Clinical Aspects of
Glucocorticoid Therapy
150
100
50
0
8:00
16:00
0:00
8:00
Time (h)
Fig. 4. Simulated endogenous cortisol concentrations after methylprednisolone 8mg once daily or 4mg twice daily, using an established model and published parameter values (see Appendix).[30]
Clin Pharmacokinet 2005; 44 (1)
86
Czock et al.
macodynamics (e.g. includes additional nongenomic mechanisms) compared with maintenance immunosuppression. Clinically, the effect of glucocorticoid pulses is more similar to an all-or-none
principle than to a steady function of dose. Some
diseases (other than those requiring emergency therapy) are treated intermittently with glucocorticoid
pulses in order to maximise the beneficial effects as
well as to minimise adverse effects.
Glucocorticoid pulses are usually administered
intravenously. However, very high oral doses (≥1g)
of prednisolone (as tablets) and methylprednisolone
succinate (as an oral solution) had maximum concentrations and area under the plasma concentration-time curves (AUCs) similar to those after
intravenous administration.[15,275,276] Therefore, oral
administration of glucocorticoids might be investigated for some indications.
7.1.1 Emergency Treatment
Antirejection therapy with intravenous glucocorticoid 1000mg pulses was first reported in patients
with kidney transplants.[277] The clinical response of
antirejection treatment correlated with the induction
of apoptosis of infiltrating lymphocytes.[278] This
mechanism might contribute to the fast clinical effect on the patient’s symptoms and objective parameters such as transplant size after such pulses.
Crescentic rapidly progressive glomerulonephritis, mainly the type not due to antiglomerular basement membrane antibodies, was treated successfully
with methylprednisolone intravenous pulse therapy
(1000 mg/day for 3–5 days[279] or 7 days[280]).
Atheroembolic renal disease, caused by cholesterol emboli, is associated with eosinophilia and
vasculitis-like histological appearance[281] and was
effectively treated by methylprednisolone pulses
(500mg for 3 days), followed by oral prednisone 0.5
mg/kg/day.[282]
Patients with diffuse alveolar haemorrhage due to
SLE, systemic vasculitis or anti-GBM (glomerular
basement membrane) nephritis such as Goodpasture’s syndrome were treated effectively with
 2005 Adis Data Information BV. All rights reserved.
methylprednisolone pulse therapy.[283,284] In a retrospective study of diffuse alveolar haemorrhage associated with bone marrow transplantation, only very
high doses of glucocorticoids were effective.[285]
Treatment with dexamethasone has been suggested for acute CNS diseases.[286,287] Dexamethasone is usually preferred for treatment of CNS
diseases, because penetration into cerebrospinal fluid is superior compared with prednisolone, as shown
in a nonhuman primate model.[288]
7.1.2 Non-Emergency Treatment
Glucocorticoids are a standard therapy for the
management of acute SLE.[289,290] Despite an increased risk of infections with glucocorticoid treatment, overall survival is improved.[291] Methylprednisolone pulses are effective[292] and there was a
more rapid improvement in renal function following
pulse methylprednisolone therapy in lupus nephritis[293,294] while adverse effects were not increased.[293-295] In patients with nonrenal lupus
erythematosus, life-threatening manifestations such
as coma, seizures or thrombocytopenia responded
better to methylprednisolone pulses than to oral
glucocorticoid protocols.[296]
Primary glomerulonephritis is a heterogeneous
group of diseases that can lead to the nephrotic
syndrome, chronic renal failure or both. IgA nephritis can be treated with methylprednisolone pulses
(1000mg for 3 days) every 2 months. The maintenance dose is administered orally on alternate
days.[297] Previous studies that did not use glucocorticoid pulses were unable to demonstrate a therapeutic effect of glucocorticoids in IgA nephritis. In
severe idiopathic childhood nephrotic syndrome,
methylprednisolone 1g/1.73m2 pulses induced a
more rapid remission of proteinuria than oral prednisolone.[298]
Glucocorticoids are a standard therapy for the
management of multiple myeloma. Very high-dose
methylprednisolone has been used in refractory or
relapsed multiple myeloma.[299]
Clin Pharmacokinet 2005; 44 (1)
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
7.2 Diseases Not Treated with Pulse Therapy
Rheumatoid arthritis is characterised by the accumulation and persistence of inflammatory cells in
synovial joints, which results in joint damage. The
anti-inflammatory and antiproliferative effects of
glucocorticoids[300] leads to a reduced rate of joint
destruction.[301]
Systemic glucocorticoids are used in the treatment of acute asthma. Oral treatment was similarly
effective compared with intravenous methylprednisolone pulses.[302] Very high doses of hydrocortisone provided no benefit compared with lower
doses.[303] Methylprednisolone is often preferred for
treatment of lung diseases because it achieves higher
concentrations in the lung compared with prednisolone (as measured in bronchoalveolar lavage fluid of
rabbits).[304]
Severe sepsis and the adult respiratory distress
syndrome involve an uncontrolled host defence response that includes inflammation, endothelial damage, enhanced coagulation, microthrombi and relative adrenal insufficiency.[305] Treatment with very
high bolus doses of methylprednisolone for 24 hours
did not improve mortality,[306,307] but prolonged
treatment with stress-dose glucocorticoids for days
to weeks was beneficial.[305,308,309]
7.3 Role of the Dosage Interval
A twice-daily glucocorticoid dosage is recommended clinically for treatment of severe diseases.[310] Daily prednisolone produced more intensive and longer sustained immunosuppressive effects (biomarker: T cells) than alternate-day
treatment in kidney transplant patients.[311] Accordingly, prolongation of the dosage interval should
lead to reduced effects. A prednisolone dosage regimen of 90mg on alternate days was less effective
than 15mg every 8 hours in patients with giant cell
arteritis.[312]
Due to the short half-life of hydrocortisone, administration three times daily might be superior to
 2005 Adis Data Information BV. All rights reserved.
87
twice-daily administration in glucocorticoid replacement therapy.[313]
Maintenance therapy of asthma is based not on
systemic, but on local (inhaled) glucocorticoid administration.[242,246] A more frequent administration
of budesonide (four times daily vs twice daily) was
superior in patients with moderate to severe asthma.[314]
7.4 Variation in Clinical Response to
Glucocorticoid Therapy
The clinical response to glucocorticoid treatment
varies considerably between patients. This variability can be due to pharmacokinetic properties, pharmacodynamic properties, or both. Higher glucocorticoid clearance could lead to lower exposure to the
drug and consequently to lower immunosuppressive
and anti-inflammatory action. For example, patients
with kidney transplants who experienced transplant
rejection had a shorter methylprednisolone halflife.[315]
A correlation between the clinical response and
the in vitro responsiveness of stimulated lymphocytes to glucocorticoid treatment has been observed.
Such a correlation might be useful to predict the
clinical response in patients with focal and segmental sclerosing glomerulonephritis,[316] with kidney
transplants,[317,318] with asthma,[319] and with rheumatoid arthritis.[320]
8. Conclusions
At one time, glucocorticoids were thought to be
qualitatively indistinguishable[321] because they act
via the same receptor, but today qualitative differences have been discovered. Many beneficial and
adverse effects of glucocorticoids are due to genomic mechanisms, but there is growing evidence that
some glucocorticoid effects are mediated by nongenomic mechanisms, especially with pulse glucocorticoid therapy. As these mechanisms can differ between the various glucocorticoids, one glucocorticoid cannot be simply replaced by another.
Clin Pharmacokinet 2005; 44 (1)
88
Czock et al.
Pharmacokinetic/pharmacodynamic models are
useful for simultaneously analysing the pharmacokinetics and pharmacodynamics of a drug and for
making predictions. For low-dose maintenance therapy with glucocorticoids, twice-daily dose fractions
might allow a lower daily dose and possibly a reduction in some adverse effects. Intravenous glucocorticoid pulses can be given for some indications with a
dose interval of 4 weeks. New pharmacokinetic/
pharmacodynamic models for glucocorticoid pulse
therapy should be developed and evaluated.
Model for Simulation
We used an indirect response model for simulation of twice-daily dose fractions of methylprednisolone (figure 3 and figure 4). The pharmacokinetic model was a one-compartment model with a
first-order formation rate and a first-order elimination rate where MPs is methylprednisolone succinate, MP is methylprednisolone, kf is the formation
rate constant, and ke is the elimination rate constant
(equation 5 and equation 6).
dMPs
= - kf · MPs
dt
Acknowledgements
(Eq. 5)
This study was supported by the European Commission
within the PharmDIS project (BMH4-CT98-9548 and IST
Craft-2001-52107). The authors have no conflicts of interest
to disclose.
Appendix
Statistical Data Synthesis
Published pharmacokinetic parameters are heterogeneous and their values vary between studies.
Therefore, a statistical data synthesis is necessary to
combine such values and estimate the population
mean.[322] In the current paper we summarised the
published values from different publications as the
pooled mean x where x1, x 2 , ... x k are the published
mean values and the total number of subjects n was
calculated as n = n1 + n2 + … + nk (equation 3).
n · x + n2 · x2 + … + nk · xk
x= 1 1
n
(Eq. 3)
The pooled standard deviation was calculated
using the published standard deviations s1, s2, … sk
(equation 4).
s
é s 2 (n − 1) + s 22 (n 2 − 1) + … + s k2 (n k - 1)ù
=ê 1 1
ú
n-k
ë
û
= kf · MPs - ke · MP
(Eq. 6)
The pharmacodynamic model for T helper cell
suppression was a precursor-dependent indirect response model as developed by Sharma et al.[273] and
Booker et al.[30] ThE are extravascular T helper cells
and Th are blood T helper cells. The rate constant kin
describes formation of new T helper cells, the timevarying rate constant kp(t) describes the migration of
T helper cells from the extravascular to the blood
compartment, the rate constant kout describes the
removal of T helper cells, and I(t) describes the
inhibitory effect of glucocorticoids on cell migration
(equation 7 and equation 8).
dThE
dt
= kin - kp (t ) · I (t ) · ThE
(Eq. 7)
dTh
= kp (t ) · I (t ) · ThE - k out · Th
dt
(Eq. 8)
The inhibitory function I(t) for the effect of
methylprednisolone was an Emax model where parameter Emax is the maximum achievable effect and
parameter CE50 is the concentration producing the
half-maximal effect (equation 9).
½
(Eq. 4)
 2005 Adis Data Information BV. All rights reserved.
dMP
dt
I (t ) = 1 -
E max · MP (t )
CE 50 + MP (t )
(Eq. 9)
Clin Pharmacokinet 2005; 44 (1)
Pharmacokinetics/Pharmacodynamics of Glucocorticoids
For the migration of T helper cells from the
extravascular to the blood compartment a periodic
function was applied where Rm is the mean input
rate, Rb is the amplitude and tz is the peak time in
relation to time zero (equation 10).
k p ( t ) = Rm
2π
+ Rb · cos éê(t - tz ) · ùú
24 û
ë
(Eq. 10)
The pharmacodynamic model for cortisol suppression used the same inhibitory function I(t). The
time-varying secretion of cortisol was described by
kin(t) and the elimination of cortisol by the rate
constant kout (equation 11).
dCort
dt
= k in (t ) · I (t ) - k out · Cort
(Eq. 11)
The input function kin(t) for secretion of cortisol
was a dual cosine model that also allows for asymmetric inputs where Tmax and Tmin are the timepoints
where the secretion is maximal and minimal, respectively (equations 12, 13 and 14).
t = 0 to Tmin
k in (t ) = Rm
é 2π · (t + 24 - Tmax ) ù
+ Rb · cos ê
ú
ë 2 · (Tmin - Tmax + 24 ) û
(Eq. 12)
t = Tmin to Tmax
k in (t ) = Rm
é 2π · (t - 2 · Tmin - Tmax )ù
+ Rb · cos ê
ú
ë 2 · (Tmax - Tmin ) û
(Eq. 13)
t = Tmax to 24 hours
k in (t ) = Rm
é 2π · (t - Tmax ) ù
+ Rb · cos ê
ú
ë2 · (Tmin - Tmax + 24 )û
(Eq. 14)
Parameter values used for the simulation were:
pharmacokinetic parameters: kf = 5.73 h–1, ke = 0.31
h–1, Vd = 80.96L; pharmacodynamic parameters for
T helper cell suppression: CE50 = 9.2 µg • L–1, Emax
= 1; system parameters of T helper cell variation: kin
= 383 cells • mm–3 • h–1, kout = 0.335 h–1, Rm =
0.088 h–1, Rb = 0.022 h–1, tz = 13.2 (24-hour clock);
 2005 Adis Data Information BV. All rights reserved.
89
pharmacodynamic parameters for cortisol suppression: CE50 = 0.446 µg • L–1, Emax = 1; system
parameters of cortisol variation: kout = 0.338 h–1,
tmin = 12.2 hours (24-hour clock), tmax = 21.4
hours (24-hour clock), Rm = 23.5 µg • L–1 • h–1, Rb
= 22.5 µg • L–1 • h–1.
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Correspondence and offprints: Dr Frieder Keller, Department of Internal Medicine, Division of Nephrology,
University Hospital Ulm, Robert-Koch-Str. 8, Ulm 89081,
Germany.
E-mail: [email protected]
Clin Pharmacokinet 2005; 44 (1)