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PHARMACOKINETICS IN CKD
R Vanholder
University Hospital, Gent,
Belgium
© 2008 Universitair Ziekenhuis Gent
MECHANISMS
OAT: organic acid transporter
P-gp: p-glycoprotein
CYP: cytochrome P
MRP: multidrugresistance
associated protein
BSEP: bile salt export pump
© 2008 Universitair Ziekenhuis Gent
Naud et al, J Clin Pharmacol, 52: 10S-22S; 2012
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CONTRIBUTORS TO PHARMACOKINETICS IN CKD
Renal clearance
Glomerulus
Tubulus
Metabolism
Enterocyte
Hepatocyte
Excretion in intestine
Direct
Biliary
Protein binding
Distribution volume
Disturbed
© 2008 Universitair
Ziekenhuis Gentgastro-intestinal motility and uptake
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CONTRIBUTORS TO PHARMACOKINETICS IN CKD
Renal clearance
Glomerulus
Tubulus
Metabolism
Enterocyte
Hepatocyte
VIRTUALLY ALL THESE FACTORS
INCREASE BIOAVAILABILITY
Excretion in intestine
Direct
Biliary
Protein binding
Distribution volume
Disturbed
© 2008 Universitair
Ziekenhuis Gentgastro-intestinal motility
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RENAL CLEARANCE
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drug
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ORGANIC ANION TRANSPORTERS
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OAT ACTIVITY IS DEPRESSED IN KIDNEY FAILURE
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Takeuchi, KI, 60: 1058-1068; 2001
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UREMIC TOXINS INHIBIT OATs
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Wang and Sweet, Biochem Pharmacol, 84: 1088-1095; 2012
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NON-RENAL CLEARANCE
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METABOLIC ACTIVITY CYPs IS DECREASED IN
CKD
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Leblond at al, JASN, 13: 1579–1585; 2002
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PROTEIN BINDING
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PROTEIN BINDING
CKD patients have low serum albumin due to inflammation, fluid
overload, malnutrition and urinary protein losses
In CKD the structure of albumin is modified
In CKD many drugs and protein bound toxins compete for protein
binding sites
All these elements tend to decrease drug protein binding, to
increase their free fraction, and to increase their activity (toxicity)
This effect is partly compensated: increased metabolism and
redistribution
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IMPORTANCE OF PROTEIN BINDING
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Vanholder et al, KI, 33: 996-1004; 1989
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IMPORTANCE OF PROTEIN BINDING
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Vanholder et al, KI, 33: 996-1004; 1989
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OTHER COMPETITORS
Indoxyl sulfate
Indole-acetic acid
P-cresylsulfate
…
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PRACTICAL CONSEQUENCES
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PRACTICAL CONSEQUENCES
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PRACTICAL CONSEQUENCES
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DISTRIBUTION VOLUME
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DISTRIBUTION VOLUME
Dose X0
IV
Vd C0
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DECREASE DITRIBUTION VOLUME IN AKI
INCREASES DIGOXIN CONCENTRATION
Nephron. 1984;37(3):190-4.
Rising serum digoxin without further dosage in acute renal failure.
Gault MH, Gallway B, Fine A, Vasdev S.
Abstract
A 73-year-old man was given a total of 1 mg of digoxin intravenously over 3 days, close to the
time that he developed acute renal failure with oligo-anuria. He received no cardiac glycosides
before or after this 3-day period. 2 days after the last dose, the serum digoxin concentration
(SDC) was 2.9 ng/ml, yet a peak value of 4.2 ng/ml was reached only 11 days later. The SDC
remained above 2 ng/ml for another week, until urine output began to increase appreciably. As
renal function improved, the SDC gradually fell to become undetectable 32 days after the last
dose. Values for apparent volume of distribution calculated from the total dose, and also
determined after injection of tritiated digoxin, suggest that the rise in SDC in the absence of
additional doses was due in large part to a decrease in the apparent volume of distribution.
Dosage and parameters of toxicity should be carefully monitored in patients receiving digoxin
who develop acute renal failure.
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INTESTINAL ABSORPTION
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INTESTINAL MOBILITY IS DECREASED IN
DIABETES
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Rana et al, Diab Tech Ther, 13: 1115-1120; 2011
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INTESTINAL MOBILITY IS DECREASED IN CKD
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Strid et al, Digestion, 13: 129-137; 2003
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MANY DIFFERENT EFFECTS
Decreased intestinal motility
Slowing down peak concntration, no change in bioavailability
Decreased gastric acidity
Due to uremia (ammonia), drugs (antacids, H2-antagonists)
Reduction bioavailability
GI edema
Cirrhosis
Cardiac failure
Reduction absorption: bioavailability furosemide from 50  10%
Sorbents
Sevelamer
All together, most elements reduce bioavailability
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ABSORPTION OF MYCOPHENOLATE MOFETYL BY
SEVELAMER
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Pieper et al, NDT, 19: 2630-2633; 2004
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THE EFFECT OF DIALYSIS
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EFFECTS OF DIALYSIS ON DRUG KINETICS
One may accept that dialysis almost always decreases drug
bioavailability and at best keeps it unmodified
Drug administration best occurs after the dialysis session
The only exception are drugs that are difficult to remove by dialysis
and of which peak concentration is more important than trough
(e.g. aminoglycosides)
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EXAMPLE: MEROPENEM
5,0
Healthy
LFHD - RRF10
LFHD - RRF0
HFHD - RRF0
4,5
Concentration (mg/L)
4,0
3,5
3,0
2,5
2,0
1,5
1,0
0,5
0,0
2400
2450
2500
2550
2600
2650
2700
2750
2800
2850
2900
2950
time (min)
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HEMODIALYSIS RESTORES ACTIVITY OF CYP3A4
© 2008 Universitair Ziekenhuis Gent
Michaud et al, J Pharmacol Sci, 108: 157-163; 2008
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CONCLUSIONS
The impact of renal failure on the many aspects of drug
pharmacokinetics is hard to predict in detail
The net effect of all influening factors is to increase bioavailability
If possible, drug treatment should be monitored by considering
plasma concentrations
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