Download Metabolism and drug interactions of 3-hydroxy-3

Eur J Clin Pharmacol (2001) 57: 357±364
DOI 10.1007/s002280100329
R EV IE W A RT I C L E
M. Igel á T. Sudhop á K.vonBergmann
Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl
coenzyme A-reductase inhibitors (statins)
Received: 26 February 2001 / Accepted in revised form: 23 May 2001 / Published online: 13 July 2001
Ó Springer-Verlag 2001
Abstract 3-Hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA)-reductase inhibitors (statins) are mainly
considered for long-term use and often constitute part of
a multiple-drug regime. Besides common adverse drug
e€ects, such as nausea, abdominal discomfort and
headaches, all statins harbour the risk of myopathy and
fatal rhabdomyolysis. Usually, the frequency of myopathy is low but the incidence increases during concomitant drug therapy. Statins do not di€er in their
pharmacodynamic property. Therefore, the di€erences
in their pharmacokinetic pro®les, i.e. anity for metabolising enzymes, constitute the rationale for choosing a
speci®c statin especially for combination therapy. In
order to point out harmful combinations of therapeutics, this review summarises the pharmacokinetic data of
six clinically used statins (atorvastatin, cerivastatin, ¯uvastatin, lovastatin, pravastatin and simvastatin) with
special regard to metabolism and drug interactions. In
summary, statins that lack a signi®cant hepatic metabolism, i.e. pravastatin, or that are metabolised by more
than one cytochrome P450 isoenzyme, i.e. ¯uvastatin, or
whose metabolism is taken over by other cytochrome
P450 isoenzymes in case of blockage of the main metabolising enzyme, i.e. cerivastatin, are the least prone to
drug interactions. Nevertheless, in case of a speci®c
concomitant drug therapy known to be associated with a
higher risk of adverse events, i.e. cyclosporin A and
statin, clinical symptoms of myopathy and biochemical
data, such as increasing serum creatine phosphokinase,
should be monitored carefully.
Keywords HMG-CoA-reductase inhibitor á
Statin á Pharmacokinetic
M. Igel á T. Sudhop á K. von Bergmann (&)
Department of Clinical Pharmacology,
University of Bonn, Sigmund-Freud-Strasse 25,
53105 Bonn, Germany
E-mail: [email protected]
Tel.: +49-228-2876080
Fax: +49-228-2876094
Introduction
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitors (statins) represent the most ecient
drugs for the treatment of hypercholesterolaemia. Plasma cholesterol is lowered due to the inhibition of
endogenous cholesterol synthesis and the subsequent
increased expression of the low-density lipoprotein
(LDL) receptor, resulting in an upregulated catabolic
rate for plasma LDL. In primary and secondary prevention studies the incidence of coronary heart disease
and mortality was signi®cantly reduced [1, 2, 3, 4, 5].
Although these drugs are generally well tolerated,
adverse events are associated with their short- and
long-term use and especially with concomitant therapy
leading to myopathy and potentially fatal rhabdomyolysis [6, 7, 8, 9, 10, 11]. Since the prevalence of
adverse events varies among the statins and since
pharmacokinetic considerations may explain these differences only in part, it is the aim of this review to
summarise the pharmacokinetic properties of statins
and to emphasise their clinically important drug
interactions.
Overview of basic pharmacokinetic properties of statins
Six statins ± lovastatin, simvastatin, pravastatin, ¯uvastatin, atorvastatin and cerivastatin ± are currently
used (Table 1). Lovastatin, simvastatin and pravastatin
are derived from Aspergillus terreus. Whereas lovastatin
is the natural product, the other two are produced by
semi-synthetic processes [12, 13, 14]. Fluvastatin, atorvastatin and cerivastatin are completely synthetic compounds. Simvastatin is the butyrate analogue of
lovastatin, and is ± like lovastatin ± a prodrug (lactone),
whereas the other statins are administered as active
compounds (acid). Pravastatin is the most hydrophilic
compound. Cerivastatin and ¯uvastatin are almost
completely absorbed after oral administration, whereas
the low extent of absorption of pravastatin is probably
CYP2C8
CYP2C9
CYP2D6
CYP3A4
Metabolites contributing
to lipid-lowering e€ect
tmax (h)
Terminal half-life (h)
Clearance (l/h/kg)
Protein binding (%)
Hepatic extraction
(% absorbed dose)
CYP substrate
Origin
Prodrug (Lactone)
Lipophilicity, C log P
(octanol/water)
Crosses blood±brain
barrier
Dosage
Absorption (%)
Bioavailability (%)
E€ect of food on
bioavailability
Yes [20, 38, 75, 81,
92, 93]
(+)
(+)
+
Yes [81]
Yes [21, 29, 75]
(+)
(+)
+
Yes [99]
5±80 mg
60±85% [77]
<5% [7]
No [7]
10±80 mg
31% [6]
<5% [6]
Yes (50% increase)
[69]
1.3±2.4 [7]
1.9±15.6 [69]
0.45 [20]
95% [7, 90]
78±87 [20]
Lactone [76]
Lactone [76]
2.8 [81]
2.5±15 [79]
0.26±1.1 [20]
95% [6]
>70% [20]
Semi-synthetic [13]
Yes
4.7 (47,860)
Simvastatin
Microbial [12]
Yes [69]
4.3 (18,620) [20]
Lovastatin
(+)
Yes, mainly inactive
[25, 26]
(+)
Clinically not relevant
[21, 38, 94, 95, 96, 97]
0.9±1.6 [78, 88]
0.8±3.0 [81]
0.81 [20]
48% [25]
66% [25]
5±40 mg
35% [78]
17% [78]
Yes (30% decrease)
[69, 84]
No [76]
Semi-synthetic [11]
No
±0.2 (0.6)
Pravastatin
+
(+)
(+)
Yes, mainly inactive
[98]
Yes [21, 35, 75, 98]
0.5±1.5 [79]
0.5±2.3 [9]
0.97 [79]
>99% [79, 91]
68 [69]
20±80 mg
98% [14]
10±35% [81]
Yes (15±25% decrease)
[69, 85, 86]
No [69]
Synthetic [14]
No
3.2 (1738)
Fluvastatin
+
Active [10, 20, 69]
Yes [75]
2±4 [69]
11±30 [80, 89]
0.25 [20]
>98% [10]
>70 [20]
10±80 mg
30% [80]
12% [10]
Yes (13% decrease)
[20, 69]
N/a
Synthetic [10]
No
4.1 (1482)
Atorvastatin
+
Active [27]
+
Yes [36, 39, 75]
0.1±0.8 mg
>98 [15]
60% [27, 82, 83]
Morning: Yes (23%
decrease) [69];
Evening: No [15, 87]
2.5±3.0 [82, 83]
2±3 [27, 83]
0.2 [27]
>99% [27, 83]
N/a
N/a
Synthetic [11]
No
1.5 (29.5)
Cerivastatin
Table 1 Pharmacokinetic data of 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins). N/a not available, tmax time to reach peak plasma concentration, CYP
cytochrome P450, C log P logarithm of the partition coecient based on octanol/water phase
358
359
due to its hydrophilicity and consequently low intestinal
permeability. The low intestinal uptake of lovastatin is
probably related to its hydrophobic properties, which
prevent complete dissolution in the intestinal ¯uid.
Concomitant food intake does not a€ect the absorption
of simvastatin and cerivastatin, at least not when low-fat
meals are consumed [7, 15]. The diurnal variation of
cholesterol synthesis leads to the recommendation that
statins when administered only once a day should be
taken at night [16].
Daily dosage ranges vary from 0.1 mg to 80 mg and
the following doses have been proposed to be approximately equipotent: 10 mg atorvastatin, 20 mg
simvastatin, 40 mg lovastatin, 40 mg pravastatin,
80 mg ¯uvastatin and 0.4 mg cerivastatin. These dose
regimens lead to an approximately 22% reduction in
total cholesterol and approximately 27% reduction in
LDL cholesterol [17]. Dose±response studies revealed a
non-linear relationship and most of the e€ectiveness is
preserved at low doses, although higher doses may
further reduce LDL cholesterol. As a rule of thumb, a
doubling of the dose causes a lowering of the cholesterol of about a further 5% in total and 7% of LDL
cholesterol [17].
cerivastatin can also be metabolised by CYP2C8
[20, 36].
Another property predicting drug interaction is the
anity of binding to cytochrome enzymes. Fluvastatin
shows high anity to CYP2C9, lovastatin and simvastatin exert moderate anity to CYP3A4 and cerivastatin has the lowest anity to CYP3A4 [21].
Therefore, ¯uvastatin is hardly displaced from CYP2C9,
for example, by diclofenac, a typical substrate of
CYP2C9 with lower binding anity. In contrast, the
metabolism of lovastatin and simvastatin may be more
easily disturbed by substrates of the same iso-enzyme,
i.e. azole antifungals such as itraconazole [37, 38]. Finally, when transformation of cerivastatin by CYP3A4
is blocked, metabolism is performed by CYP2C8 [33,
39].
All in all, the available data clearly indicate that
biotransformation by microsomal cytochrome enzymes
is the predominant metabolic pathway in ®ve of six
statins. Induction or inhibition of cytochrome isoenzymes often accounts for drug interactions and the
majority of clinically used drugs interact with CYP.
This information may in¯uence the choice of drugs
considered for combination therapy.
Metabolism
Drug interactions
Lovastatin and simvastatin are administered as lactone
prodrugs and, consequently, they are activated by hydrolysis to their correspondent hydroxyl acids by nonspeci®c carboxyesterase in the intestinal wall, liver and
to some extent in plasma. Therefore, variations in
carboxyesterase activity might in¯uence the individual
response to these statins [18]. Due to their rapid
metabolism in gut and liver, the systemic bioavailability
is relatively low, but does not correspond with their
biological activity, since their main site of action is in the
hepatocyte.
Concerning drug interactions, the metabolism by
cytochrome P450 enzymes (CYP) seems to be the most
important [19, 20, 21]. These enzymes are expressed
mainly in liver microsomes and in gut wall [22]. The
CYP3A iso-enzymes are the most abundant and account
for approximately 30% in liver and 80% in small
intestinal mucosa [23]. In addition to CYP3A4, three
distinct cytochromes, CYP2C8, CYP2C9 and CYP2D6,
play an important role in the metabolism of statins.
With the exception of pravastatin, all statins
undergo extensive microsomal metabolism by CYP
enzymes. Pravastatin is transformed enzymatically in
the liver cytosol [20, 24, 25, 26]. CYP3A species, especially CYP3A4, are the major enzymes metabolising the
lactone form of lovastatin and simvastatin. Atorvastatin and cerivastatin are also primarily transformed by
CYP3A4 [27, 28, 29, 30, 31, 32, 33]. CYP2C9 is the
major enzyme metabolising ¯uvastatin, whereas
CYP3A4, CYP2C8 and CYP2D6 may also transform
¯uvastatin, albeit to a lesser extent [34, 35]. Similarly,
Drug interactions with statins are described, for example, for the immunosuppressants cyclosporin A [40, 41,
42, 43, 44, 45, 46] and tacrolimus [47, 48, 49, 50], for
azole antifungals such as itraconazole, ketoconazole and
¯uconazole [38, 51, 52, 53, 54, 55], for macrolide antibiotics such as eythromycin [56, 57, 58], for lipid lowering ®brates such as gem®brozil [57, 59, 60, 61, 62, 63,
64, 65], for nicotinic acid derivatives [41, 57, 66, 67], for
protease inhibitors [19], for the anticoagulant warfarin
[21, 68] and for digoxin [57].
Pathophysiology
Skeletal muscle toxicity is the predominant serious
adverse event following statin treatment [69, 70].
Myopathy is a rare, but severe, side e€ect de®ned by
myalgia or weakness and a more than tenfold increase
in creatine phosphokinase activity [71]. Mevalonic acid
formation is inhibited in striated muscle. Subsequently,
there is a lack of cholesterol precursors produced from
mevalonic acid. These are important for several cell
functions and serve, for example, glycosylation of cell
surface proteins, electron transfer during mitochondrial
membranes and post-translational modi®cation of regulatory proteins [72]. Myopathy can progress to
rhabdomyolysis which ®nally may result in renal failure. The incidence of myopathy or rhabdomyolysis is
dose dependent and interference with statin metabolism
is the most likely mechanism to increase their plasma
concentrations.
360
Immunosuppressants
Cyclosporin A and tacrolimus are metabolised in the
liver and small intestine by CYP3A4. Therefore, the
likelihood of drug interaction caused by concomitant
statin treatment can be divided into four di€erent
groups:
1. Lovastatin, simvastatin, atorvastatin: as they are
solely transformed by CYP3A4, they bear the highest
risk of skeletal muscle toxicity.
2. Cerivastatin: due to low binding anity to CYP3A4
and alternative metabolism by CYP2C8, the risk of
myotoxicity is lower than in group 1.
3. Fluvastatin: more than 90% is biotransformed by
CYP2C9. Despite a small increase in ¯uvastatin
plasma concentrations following concomitant therapy with cyclosporin A, myotoxicity has not been
reported.
4. Pravastatin: most of the drug is eliminated
unchanged and derivatives in plasma or urine are
generated mainly by phase-II metabolism and
degradation. Inhibition of CYP3A4 does not signi®cantly increase plasma concentrations. Nevertheless,
an increased pravastatin area under the plasma concentration±time curve (AUC, 5- to 23-fold) has been
reported [73, 74] and the underlying mechanism is
believed to be on the level of biliary secretion.
However, interactions with cyclosporin A have not
been reported [57].
Azole antifungals
Itraconazole, ketoconazole and ¯uconazole are strong
inhibitors of CYP3A. Therefore, combination therapy should be performed with either ¯uvastatin or pravastatin.
Macrolide antibiotics
Eythromycin and clarithromycin are weak inhibitors of
CYP3A isoenzymes. Nevertheless, cases of increased
bioavailability of statins as well as cases of myositis and
rhabdomyolysis have been reported with concurrent use
of lovastatin and simvastatin. As data concerning atorvastatin and cerivastatin are not available, these drugs
are also not recommended for combination therapy.
Fibrates
Interactions between statins and ®bric acid derivatives,
such as gem®brozil, deserve particular attention as myopathy can occur with either drug alone. Liver function
can be impaired by ®brates resulting in diminished
hepatic clearance of statins and, consequently, higher
plasma levels of statins. Therefore, patients with impaired liver function should not receive combination
therapy. Furthermore, ®brates are primarily excreted
renally, and renal impairment may increase the risk of
myopathy. Recently, the e€ect of gem®brozil on the
pharmacokinetics of simvastatin was investigated and
revealed that gem®brozil increases the plasma concentration of active simvastatin acid without inhibiting
CYP3A4 [65]. Thus, the interactions seem to be pharmacodynamic and pharmacokinetic in nature and,
unfortunately, have been reported with each statin.
Especially when co-administered with cerivastatin,
gem®brozil seems to induce more myopathic interactions than other ®brates. Thus, concomitant use of
gem®brozil and cerivastatin is not recommended [100].
However, there is no pharmacokinetic interaction
between cerivastatin and feno®brate [27].
Nicotinic acid derivatives
The mechanism behind the interaction of nicotinic acid
and lovastatin is not completely understood, but myopathy has been reported in 2% of patients receiving
this combination. Possibly, the depletion of cholesterol
might destabilise sarcolemmic membranes and increase
membrane ¯uidity. Elevated plasma concentrations of
lovastatin are not reported. No interactions have been
observed when nicotinic acid derivatives were administered with simvastatin, pravastatin or ¯uvastatin.
Coumarin anticoagulants
Although the mechanism of interaction between warfarin and statins is uncertain, reduction of warfarin dosage
is sometimes required to achieve an appropriate level of
anticoagulation. Warfarin is a racemic compound and
metabolism of the (S)-enantiomer is primarily catalysed
by CYP2C9, while (R)-warfarin undergoes transformation primarily by CYP3A4. Given that these two
isoenzymes are involved in metabolism, competition
with lovastatin, simvastatin, cerivastatin, atorvastatin
and ¯uvastatin may be a contributing factor. The anticoagulant e€ects of warfarin are not known to be altered
by pravastatin.
Calcium-channel antagonists and digoxin
Diltiazem and verapamil are weak inhibitors of
CYP3A4 and statins metabolised mainly by this enzyme
should therefore be avoided. Mibefradil, a calciumchannel antagonist, strongly suppressed, at therapeutically relevant concentrations, the metabolism in human
liver microsomes of simvastatin, lovastatin, atorvastatin
and cerivastatin through its inhibitory e€ects on
CYP3A4/5, while the e€ects of mibefradil on ¯uvastatin,
361
a substrate for CYP2C8/9, in this system were minimal.
Since mibefradil was a potent mechanism-based inhibitor of CYP3A4/5, it was anticipated that clinically signi®cant drug±drug interactions would likely ensue when
mibefradil was co-administered with agents that are
cleared primarily by CYP3A-mediated pathways [75].
This is the probable reason for withdrawal of this calcium-channel blocker from the market. The only likely
clinical interaction between statins and digoxin is for
simvastatin, which caused slight elevation in plasma
digoxin concentrations.
for early symptoms of myopathy, administration of
statins and potentially interfering drugs at least 3 h
apart, choice of statin with accordant pharmacokinetic
pro®le for concomitant therapy. In contrast, pravastatin
is water-soluble and does not undergo metabolism via
CYP to any signi®cant extent. In patients receiving
complex pharmacotherapy, pravastatin would be a good
choice due to its lack of signi®cant hepatic metabolism
and consequent lack of clinically signi®cant drug±drug
interactions. However, the above-mentioned strategies
should also be followed.
Protease inhibitors
Acknowledgement Supported by a grant from the Bundesministerium fuÈr Bildung, Forschung, Wissenschaft und Technologie
(01EC9402).
The protease inhibitors indinavir, nel®navir, ritonavir
and saquinavir are substrates and inhibitors of
CYP3A4. In addition, ritonavir is also a signi®cant inhibitor of CYP2D6. Concomitant administration of ritonavir and lovastatin increases the AUC of lovastatin
threefold. Therefore, giving statins with inhibitory potential for CYP3A4 and/or CYP2D6 should be avoided
or dosage of statins should be reduced to avoid the
potential for rhabdomyolysis. Although little information is available, pravastatin is to be preferred and
cerivastatin might be a second-line choice due to compensatory metabolism by CYP2C8.
Nutritional products
Grapefruit juice increases the oral bioavailability of
several drugs known to be metabolised by CYP3A4. The
underlying mechanism is a furanocoumarin (dihydroxybergamottin, DHB) present in grapefruit juice that
causes inactivation of CYP3A4 and subsequent accelerated degradation of the enzyme. As the amount of
DHB varies greatly between di€erent brands, the result
does not have the predictability to allow a safe and effective reduction in the dose of statin. Thus, those statins
metabolised mainly by CYP3A4 should not be taken
together with grapefruit juice.
Conclusion
Pharmacokinetic drug±drug interactions in¯uencing
drug ecacy, tolerability and compliance are both
common and of more clinical relevance than often
anticipated. Unfortunately, it is not possible to predict
which patients will manifest clinically important interactions, and it is this unpredictability that emphasises
the need for caution. Especially in patients requiring
long-term therapy with drugs that are substrates or
inhibitors of CYP3A and/or CYP2C, the di€erent
pharmacokinetic pro®les among the statins should be
carefully considered. Concomitant therapy with these
substrates should follow certain strategies to reduce the
risk of skeletal muscle toxicity: close clinical monitoring
References
1. Downs JR, Clear®eld M, Weis S, Whitney E, Shapiro DR,
Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM,
Jr (1998) Primary prevention of acute coronary events with
lovastatin in men and women with average cholesterol levels:
results of AFCAPS/TexCAPS. Air Force/Texas Coronary
Atherosclerosis Prevention Study. JAMA 279:1615±1622
2. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR,
MacFarlane PW, McKillop JH, Packard CJ (1995) Prevention
of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention
Study Group. N Engl J Med 333:1301±1307
3. Waters D, Higginson L, Gladstone P, Kimball B, Le May M,
Boccuzzi SJ, Lesperance J (1994) E€ects of monotherapy with
an HMG-CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography. The Canadian Coronary Atherosclerosis Intervention
Trial. Circulation 89:959±968
4. Sacks FM, Pfe€er MA, Moye LA, Rouleau JL, Rutherford
JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC,
Davis BR, Braunwald E (1996) The e€ect of pravastatin on
coronary events after myocardial infarction in patients with
average cholesterol levels. Cholesterol and Recurrent Events
Trial investigators. N Engl J Med 335:1001±1009
5. The Scandinavian Simvastatin Survival Study Group (1994)
Randomised trial of cholesterol lowering in 4444 patients with
coronary heart disease: the Scandinavian Simvastatin Survival
Study (4 S). Lancet 344:1383±1389
6. Henwood JM, Heel RC (1988) Lovastatin. A preliminary
review of its pharmacodynamic properties and therapeutic use
in hyperlipidaemia. Drugs 36:429±454
7. Todd PA, Goa KL (1990) Simvastatin. A review of its pharmacological properties and therapeutic potential in hypercholesterolaemia. Drugs 40:583±607
8. Haria M, McTavish D (1997) Pravastatin. A reappraisal of its
pharmacological properties and clinical e€ectiveness in the
management of coronary heart disease. Drugs 53:299±336
9. Plosker GL, Wagsta€ AJ (1996) Fluvastatin: a review of its
pharmacology and use in the management of hypercholesterolaemia. Drugs 51:433±459
10. Lea AP, McTavish D (1997) Atorvastatin. A review of its
pharmacology and therapeutic potential in the management of
hyperlipidaemias. Drugs 53:828±847
11. Bischo€ H, Heller AH (1998) Preclinical and clinical pharmacology of cerivastatin. Am J Cardiol 82:18J±25J
12. Alberts AW, Chen J, Kuron G, Hunt V, Hu€ J, Ho€man C,
Rothrock J, Lopez M, Joshua H, Harris E, Patchett A,
Monaghan R, Currie S, Stapley E, Albers-Schonberg G,
Hensens O, Hirsh®eld J, Hoogsteen K, Liesch J, Springer J
(1980) Mevinolin: a highly potent competitive inhibitor of
362
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 77:3957±3961
Ho€man WF, Alberts AW, Anderson PS, Chen JS, Smith RL,
Willard AK (1986) 3-Hydroxy-3-methylglutaryl-coenzyme A
reductase inhibitors. 4. Side chain ester derivatives of mevinolin. J Med Chem 29:849±852
Blum CB (1994) Comparison of properties of four inhibitors of
3-hydroxy-3-methylglutaryl-coenzyme A reductase. Am J
Cardiol 73:3D±11D
MuÈck W, Ochmann K, Mazzu A, Lettieri J (1999) Biopharmaceutical pro®le of cerivastatin: a novel HMG-CoA reductase inhibitor, J Int Med Res 27:107±114
Parker TS, McNamara DJ, Brown CD, Kolb R, Ahrens EH,
Jr Alberts AW, Tobert J, Chen J, De Schepper PJ (1984)
Plasma mevalonate as a measure of cholesterol synthesis in
man. J Clin Invest 74:795±804
Roberts WC (1997) The rule of 5 and the rule of 7 in lipidlowering by statin drugs. Am J Cardiol 80:106±107
Tang BK, Kalow W (1995) Variable activation of lovastatin by
hydrolytic enzymes in human plasma and liver. Eur J Clin
Pharmacol 47:449±451
Michalets EL (1998) Update: clinically signi®cant cytochrome
P-450 drug interactions. Pharmacotherapy 18:84±112
Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R,
Bernini F (1999) New insights into the pharmacodynamic and
pharmacokinetic properties of statins. Pharmacol Ther
84:413±428
Transon C, Leemann T, Dayer P (1996) In vitro comparative
inhibition pro®les of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by
HMG-CoA reductase inhibitors. Eur J Clin Pharmacol
50:209±215
Kolars JC, Lown KS, Schmiedlin-Ren P, Ghosh M, Fang C,
Wrighton SA, Merion RM, Watkins PB (1994) CYP3A gene
expression in human gut epithelium. Pharmacogenetics
4:247±259
Guengerich FP (1999) Cytochrome P-450 3A4: regulation and
role in drug metabolism. Annu Rev Pharmacol Toxicol 39:1±17
Everett DW, Chando TJ, Didonato GC, Singhvi SM, Pan HY,
Weinstein SH (1991) Biotransformation of pravastatin sodium
in humans. Drug Metab Dispos 19:740±748
Quion JA, Jones PH (1994) Clinical pharmacokinetics of
pravastatin. Clin Pharmacokinet 27:94±103
Kitazawa E, Tamura N, Iwabuchi H, Uchiyama M, Muramatsu S, Takahagi H, Tanaka M (1993) Biotransformation of
pravastatin sodium (I). Mechanisms of enzymatic transformation and epimerization of an allylic hydroxy group of pravastatin sodium. Biochem Biophys Res Commun 192:597±602
MuÈck W (2000) Clinical pharmacokinetics of cerivastatin. Clin
Pharmacokinet 39:99±116
Cheng H, Rogers JD, Sweany AE, Dobrinska MR, Stein EA,
Tate AC, Amin RD, Quan H (1992) In¯uence of age and
gender on the plasma pro®les of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitory activity following multiple doses of lovastatin and simvastatin. Pharm
Res 9:1629±1633
Wang RW, Kari PH, Lu AY, Thomas PE, Guengerich FP,
Vyas KP (1991) Biotransformation of lovastatin. IV. Identi®cation of cytochrome P450 3A proteins as the major
enzymes responsible for the oxidative metabolism of lovastatin
in rat and human liver microsomes. Arch Biochem Biophys
290:355±361
Stern RH, Gibson DM, Whit®eld LR (1998) Cimetidine does
not alter atorvastatin pharmacokinetics or LDL-cholesterol
reduction. Eur J Clin Pharmacol 53:475±478
Stern R, Abel R, Gibson GL, Besserer J (1997) Atorvastatin
does not alter the anticoagulant activity of warfarin. J Clin
Pharmacol 37:1062±1064
Yang BB, Hounslow NJ, Sedman AJ, Forgue ST (1996) E€ects
of atorvastatin, an HMG-CoA reductase inhibitor, on hepatic
oxidative metabolism of antipyrine. J Clin Pharmacol
36:356±360
33. Sachse R, Brendel E, Muck W, Rohde G, Ochmann K,
Horstmann R, Kuhlmann J (1998) Lack of drug-drug interaction between cerivastatin and nifedipine. Int J Clin Pharmacol Ther 36:409±413
34. Fischer V, Johanson L, Heitz F, Tullman R, Graham E, Baldeck JP, Robinson WT (1999) The 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitor ¯uvastatin: e€ect on human
cytochrome P-450 and implications for metabolic drug interactions. Drug Metab Dispos 27:410±416
35. Transon C, Leemann T, Vogt N, Dayer P (1995) In vivo inhibition pro®le of cytochrome P450 TB (CYP2C9) by (‹)¯uvastatin. Clin Pharmacol Ther 58:412±417
36. Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern
A, Ploschke J, Radtke M (1997) Metabolism of cerivastatin by
human liver microsomes in vitro. Characterization of primary
metabolic pathways and of cytochrome P450 isozymes involved. Drug Metab Dispos 25:321±331
37. Kivisto KT, Kantola T, Neuvonen PJ (1998) Di€erent e€ects
of itraconazole on the pharmacokinetics of ¯uvastatin and
lovastatin. Br J Clin Pharmacol 46:49±53
38. Neuvonen PJ, Kantola T, Kivisto KT (1998) Simvastatin but
not pravastatin is very susceptible to interaction with the
CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther
63:332±341
39. MuÈck W, Ochmann K, Rohde G, Unger S, Kuhlmann J (1998)
In¯uence of erythromycin pre- and co-treatment on single-dose
pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin. Eur J Clin Pharmacol 53:469±473
40. Corpier CL, Jones PH, Suki WN, Lederer ED, Quinones MA,
Schmidt SW, Young JB (1988) Rhabdomyolysis and renal
injury with lovastatin use. Report of two cases in cardiac
transplant recipients, JAMA 260:239±241
41. Tobert JA (1988) Ecacy and long-term adverse e€ect pattern
of lovastatin. Am J Cardiol 62:28J±34J
42. Vanhaecke J, Van Cleemput J, Van Lierde J, Daenen W, De
Geest H (1994) Safety and ecacy of low dose simvastatin in
cardiac transplant recipients treated with cyclosporine.
Transplantation 58:42±45
43. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Chia D, Terasaki PI, Sabad A, Cogert GA,
et al (1995) E€ect of pravastatin on outcomes after cardiac
transplantation. N Engl J Med 333:621±627
44. Maltz HC, Balog DL, Cheigh JS (1999) Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine. Ann Pharmacother 33:1176±1179
45. MuÈck W, Mai I, Fritsche L, Ochmann K, Rohde G, Unger S,
Johne A, Bauer S, Budde K, Roots I, Neumayer HH, Kuhlmann J (1999) Increase in cerivastatin systemic exposure after
single and multiple dosing in cyclosporine-treated kidney
transplant recipients. Clin Pharmacol Ther 65:251±261
46. Rodriguez ML, Mora C, Navarro JF (2000) Cerivastatininduced rhabdomyolysis. Ann Intern Med 132:598
47. Yamada H, Kotaki H, Sawada Y, Iga T (1998) Simvastatintacrolimus and simvastatin-cyclosporin interactions in rats.
Biopharm Drug Dispos 19:279±284
48. Meiser BM, Wenke K, Thiery J, Wolf S, Devens C, Seidel D,
Hammer C, Billingham ME, Reichart B (1993) Simvastatin
decreases accelerated graft vessel disease after heart transplantation in an animal model. Transplant Proc 25:2077±2079
49. Kobashigawa JA (1999) Postoperative management following
heart transplantation. Transplant Proc 31:2038±2046
50. Burrows L, Knight R, Genyk Y, Schwartz B, Moran V,
Anand R (1998) Conversion to tacrolimus to ameliorate
cyclosporine toxicity in kidney recipients. Transplant Proc
30:2030±2032
51. Lees RS, Lees AM (1995) Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med 333:664±665
52. Neuvonen PJ, Jalava KM (1996) Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin
acid. Clin Pharmacol Ther 60:54±61
363
53. Venkatakrishnan K, von Moltke LL, Greenblatt DJ (2000)
E€ects of the antifungal agents on oxidative drug metabolism:
clinical relevance. Clin Pharmacokinet 38:111±180
54. Gilad R, Lampl Y (1999) Rhabdomyolysis induced by simvastatin and ketoconazole treatment. Clin Neuropharmacol
22:295±297
55. Stalenhoef AF, Stuyt PM, de Graaf J (1997) E€ects of
ketoconazole on plasma lipids and lipoprotein (a) in familial
hypercholesterolaemia, compared with simvastatin. Neth J
Med 51:10±15
56. Ayanian JZ, Fuchs CS, Stone RM (1988) Lovastatin and
rhabdomyolysis. Ann Intern Med 109:682±683
57. Garnett WR (1995) Interactions with hydroxymethylglutarylcoenzyme A reductase inhibitors. Am J Health Syst Pharm
52:1639±1645
58. Spach DH, Bauwens JE, Clark CD, Burke WG (1991)
Rhabdomyolysis associated with lovastatin and erythromycin
use. West J Med 154:213±215
59. Ahmad S (1990) Gem®brozil interaction with warfarin sodium
(coumadin). Chest 98:1041±1042
60. Illingworth DR, Tobert JA (1994) A review of clinical trials
comparing HMG-CoA reductase inhibitors. Clin Ther 16:366±
385
61. Shepherd J (1995) Fibrates and statins in the treatment of
hyperlipidaemia: an appraisal of their ecacy and safety. Eur
Heart J 16:5±13
62. Tal A, Rajeshawari M, Isley W (1997) Rhabdomyolysis
associated with simvastatin-gem®brozil therapy. South Med J
90:546±547
63. Pogson GW, Kindred LH, Carper BG (1999) Rhabdomyolysis
and renal failure associated with cerivastatin-gem®brozil
combination therapy. Am J Cardiol 83:1146
64. Duell PB, Connor WE, Illingworth DR (1998) Rhabdomyolysis after taking atorvastatin with gem®brozil. Am J Cardiol
81:368±369
65. Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen
PJ (2000) Plasma concentrations of active simvastatin acid are
increased by gem®brozil. Clin Pharmacol Ther 68:122±129
66. Norman DJ, Illingworth DR, Munson J, Hosenpud J (1988)
Myolysis and acute renal failure in a heart-transplant recipient
receiving lovastatin. N Engl J Med 318:46±47
67. Reaven P, Witztum JL (1988) Lovastatin, nicotinic acid, and
rhabdomyolysis. Ann Intern Med 109:597±598
68. Ahmad S (1990) Lovastatin. Warfarin interaction. Arch Intern
Med 150:2407
69. Christians U, Jacobsen W, Floren LC (1998) Metabolism and
drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A
reductase inhibitors in transplant patients: are the statins
mechanistically similar? Pharmacol Ther 80:1±34
70. Hsu I, Spinler SA, Johnson NE (1995) Comparative evaluation
of the safety and ecacy of HMG-CoA reductase inhibitor
monotherapy in the treatment of primary hypercholesterolemia. Ann Pharmacother 29:743±759
71. Sylvain-Moore H, Worden JP, Jr (1991) Lovastatin-associated
rhabdomyolysis. Heart Lung 20:464±466
72. Brown MS, Goldstein JL (1980) Multivalent feedback
regulation of HMG CoA reductase, a control mechanism
coordinating isoprenoid synthesis and cell growth. J Lipid Res
21:505±517
73. Olbricht C, Wanner C, Eisenhauer T, Kliem V, Doll R,
Boddaert M, O'Grady P, Krekler M, Mangold B, Christians U
(1997) Accumulation of lovastatin, but not pravastatin, in the
blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Ther 62:311±321
74. Kliem V, Wanner C, Eisenhauer T, Olbricht CJ, Doll R,
Boddaert M, O'Grady P, Krekler M, Mangold B, Christians U
(1996) Comparison of pravastatin and lovastatin in renal
transplant patients receiving cyclosporine. Transplant Proc
28:3126±3128
75. Prueksaritanont T, Ma B, Tang C, Meng Y, Assang C, Lu P,
Reider PJ, Lin JH, Baillie TA (1999) Metabolic interactions
between mibefradil and HMG-CoA reductase inhibitors: an in
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
vitro investigation with human liver preparations. Br J Clin
Pharmacol 47:291±298
Saheki A, Terasaki T, Tamai I, Tsuji A (1994) In vivo and in
vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Pharm
Res 11:305±311
Plosker GL, McTavish D (1995) Simvastatin. A reappraisal of
its pharmacology and therapeutic ecacy in hypercholesterolaemia. Drugs 50:334±363
Singhvi SM, Pan HY, Morrison RA, Willard DA (1990) Disposition of pravastatin sodium, a tissue-selective HMG-CoA
reductase inhibitor, in healthy subjects. Br J Clin Pharmacol
29:239±243
Tse FL, Ja€e JM, Troendle A (1992) Pharmacokinetics of
¯uvastatin after single and multiple doses in normal volunteers.
J Clin Pharmacol 32:630±638
Posvar EL, Radulovic LL, Cilla DD Jr, Whit®eld LR, Sedman
AJ (1996) Tolerance and pharmacokinetics of single-dose
atorvastatin, a potent inhibitor of HMG-CoA reductase, in
healthy subjects. J Clin Pharmacol 36:728±731
Lennernas H, Fager G (1997) Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and di€erences. Clin Pharmacokinet 32:403±425
MuÈck W, Ritter W, Ochmann K, Unger S, Ahr G, Wingender
W, Kuhlmann J (1997) Absolute and relative bioavailability of
the HMG-CoA reductase inhibitor cerivastatin. Int J Clin
Pharmacol Ther 35:255±260
McClellan KJ, Wiseman LR, McTavish D (1998) Cerivastatin.
Drugs 55:415±420
Pan HY, DeVault AR, Brescia D, Willard DA, McGovern
ME, Whigan DB, Ivashkiv E (1993) E€ect of food on pravastatin pharmacokinetics and pharmacodynamics. Int J Clin
Pharmacol Ther Toxicol 31:291±294
Smith HT, Jokubaitis LA, Troendle AJ, Hwang DS, Robinson
WT (1993) Pharmacokinetics of ¯uvastatin and speci®c drug
interactions, Am J Hypertens 6:375S±382S
Deslypere JP (1994) Clinical implications of the biopharmaceutical properties of ¯uvastatin. Am J Cardiol 73:12D±17D
MuÈck W, Frey R, Unger S, Voith B (2000) Pharmacokinetics
of cerivastatin when administered under fasted and fed conditions in the morning or evening. Int J Clin Pharmacol Ther
38:298±303
Pan HY, DeVault AR, Swites BJ, Whigan D, Ivashkiv E,
Willard DA, Brescia D (1990) Pharmacokinetics and pharmacodynamics of pravastatin alone and with cholestyramine in
hypercholesterolemia. Clin Pharmacol Ther 48:201±207
Cilla DD Jr, Whit®eld LR, Gibson DM, Sedman AJ, Posvar EL
(1996) Multiple-dose pharmacokinetics, pharmacodynamics,
and safety of atorvastatin, an inhibitor of HMG-CoA
reductase, in healthy subjects. Clin Pharmacol Ther 60:687±695
Mauro VF (1993) Clinical pharmacokinetics and practical
applications of simvastatin. Clin Pharmacokinet 24:195±202
Tse FL, Nickerson DF, Yardley WS (1993) Binding of
¯uvastatin to blood cells and plasma proteins. J Pharm Sci
82:942±947
Kantola T, Kivisto KT, Neuvonen PJ (1998) Erythromycin
and verapamil considerably increase serum simvastatin and
simvastatin acid concentrations. Clin Pharmacol Ther 64:177±
182
Prueksaritanont T, Gorham LM, Ma B, Liu L, Yu X, Zhao JJ,
Slaughter DE, Arison BH, Vyas KP (1997) In vitro metabolism
of simvastatin in humans [SBT] identi®cation of metabolizing
enzymes and e€ect of the drug on hepatic P450s. Drug Metab
Dispos 25:1191±1199
Jacobsen W, Kirchner G, Hallensleben K, Mancinelli L, Deters
M, Hackbarth I, Baner K, Benet LZ, Sewing KF, Christians U
(1999) Small intestinal metabolism of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin and comparison with pravastatin. J Pharmacol Exp Ther 291:131±139
Jacobsen W, Kirchner G, Hallensleben K, Mancinelli L, Deters M, Hackbarth I, Benet LZ, Sewing KF, Christians U
(1999) Comparison of cytochrome P-450-dependent metabo-
364
lism and drug interactions of the 3-hydroxy-3-methylglutarylCoA reductase inhibitors lovastatin and pravastatin in the
liver. Drug Metab Dispos 27:173±179
96. Becquemont L, Funck-Brentano C, Jaillon P (1999) Mibefradil, a potent CYP3A inhibitor, does not alter pravastatin
pharmacokinetics. Fundam Clin Pharmacol 13:232±236
97. Azie NE, Brater DC, Becker PA, Jones DR, Hall SD (1998)
The interaction of diltiazem with lovastatin and pravastatin.
Clin Pharmacol Ther 64:369±377
98. Dain JG, Fu E, Gorski J, Nicoletti J, Scallen TJ (1993) Biotransformation of ¯uvastatin sodium in humans. Drug Metab
Dispos 21:567±572
99. Duggan DE, Chen IW, Bayne WF, Halpin RA, Duncan CA,
Schwartz MS, Stubbs RJ, Vickers S (1989) The physiological
disposition of lovastatin. Drug Metab Dispos 17:166±173
100. Bayer AG (2001) Manufacturer's ``Dear Doctor'' Letter
[German]. Bayer, Leverkusen