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© 2008 Universitair Ziekenhuis Gent
PHARMACOKINETICS IN CKD
R Vanholder
University Hospital, Gent,
Belgium
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22© 2008 Universitair Ziekenhuis Gent
MECHANISMS
Naud et al, J Clin Pharmacol, 52: 10S-22S; 2012
OAT: organic acid transporterP-gp: p-glycoproteinCYP: cytochrome PMRP: multidrugresistance associated proteinBSEP: bile salt export pump
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33© 2008 Universitair Ziekenhuis Gent
CONTRIBUTORS TO PHARMACOKINETICS IN CKD
Renal clearanceGlomerulus
Tubulus
MetabolismEnterocyte
Hepatocyte
Excretion in intestineDirect
Biliary
Protein binding
Distribution volume
Disturbed gastro-intestinal motility and uptake
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44© 2008 Universitair Ziekenhuis Gent
CONTRIBUTORS TO PHARMACOKINETICS IN CKD
Renal clearanceGlomerulus
Tubulus
MetabolismEnterocyte
Hepatocyte
Excretion in intestineDirect
Biliary
Protein binding
Distribution volume
Disturbed gastro-intestinal motility
VIRTUALLY ALL THESE FACTORSINCREASE BIOAVAILABILITY
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© 2008 Universitair Ziekenhuis Gent
RENAL CLEARANCE
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66© 2008 Universitair Ziekenhuis Gent
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77© 2008 Universitair Ziekenhuis Gent
drug
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88© 2008 Universitair Ziekenhuis Gent
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99© 2008 Universitair Ziekenhuis Gent
ORGANIC ANION TRANSPORTERS
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1010© 2008 Universitair Ziekenhuis Gent
OAT ACTIVITY IS DEPRESSED IN KIDNEY FAILURE
Takeuchi, KI, 60: 1058-1068; 2001
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1111© 2008 Universitair Ziekenhuis Gent
UREMIC TOXINS INHIBIT OATs
Wang and Sweet, Biochem Pharmacol, 84: 1088-1095; 2012
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© 2008 Universitair Ziekenhuis Gent
NON-RENAL CLEARANCE
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1313© 2008 Universitair Ziekenhuis Gent
METABOLIC ACTIVITY CYPs IS DECREASED IN CKD
Leblond at al, JASN, 13: 1579–1585; 2002
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© 2008 Universitair Ziekenhuis Gent
PROTEIN BINDING
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1515© 2008 Universitair Ziekenhuis Gent
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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1616© 2008 Universitair Ziekenhuis Gent
IMPORTANCE OF PROTEIN BINDING
Vanholder et al, KI, 33: 996-1004; 1989
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1717© 2008 Universitair Ziekenhuis Gent Vanholder et al, KI, 33: 996-1004; 1989
IMPORTANCE OF PROTEIN BINDING
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1818© 2008 Universitair Ziekenhuis Gent
OTHER COMPETITORS
Indoxyl sulfate
Indole-acetic acid
P-cresylsulfate
…
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1919© 2008 Universitair Ziekenhuis Gent
PRACTICAL CONSEQUENCES
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2020© 2008 Universitair Ziekenhuis Gent
PRACTICAL CONSEQUENCES
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2121© 2008 Universitair Ziekenhuis Gent
PRACTICAL CONSEQUENCES
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© 2008 Universitair Ziekenhuis Gent
DISTRIBUTION VOLUME
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2323© 2008 Universitair Ziekenhuis Gent
Vd C0
Dose X0 IV
DISTRIBUTION VOLUME
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2424© 2008 Universitair Ziekenhuis Gent
DECREASE DITRIBUTION VOLUME IN AKI INCREASES DIGOXIN CONCENTRATIONNephron. 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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© 2008 Universitair Ziekenhuis Gent
INTESTINAL ABSORPTION
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2626© 2008 Universitair Ziekenhuis Gent
INTESTINAL MOBILITY IS DECREASED IN DIABETES
Rana et al, Diab Tech Ther, 13: 1115-1120; 2011
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2727© 2008 Universitair Ziekenhuis Gent
INTESTINAL MOBILITY IS DECREASED IN CKD
Strid et al, Digestion, 13: 129-137; 2003
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2828© 2008 Universitair Ziekenhuis Gent
MANY DIFFERENT EFFECTS
Decreased intestinal motilitySlowing down peak concntration, no change in bioavailability
Decreased gastric acidityDue to uremia (ammonia), drugs (antacids, H2-antagonists)
Reduction bioavailability
GI edemaCirrhosis
Cardiac failure
Reduction absorption: bioavailability furosemide from 50 10%
SorbentsSevelamer
All together, most elements reduce bioavailability
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2929© 2008 Universitair Ziekenhuis Gent
ABSORPTION OF MYCOPHENOLATE MOFETYL BY SEVELAMER
Pieper et al, NDT, 19: 2630-2633; 2004
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© 2008 Universitair Ziekenhuis Gent
THE EFFECT OF DIALYSIS
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3131© 2008 Universitair Ziekenhuis Gent
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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3232© 2008 Universitair Ziekenhuis Gent
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
4,0
4,5
5,0
2400 2450 2500 2550 2600 2650 2700 2750 2800 2850 2900 2950
Co
nce
ntr
ati
on
(m
g/L)
time (min)
HealthyLFHD - RRF10LFHD - RRF0HFHD - RRF0
EXAMPLE: MEROPENEM
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3333© 2008 Universitair Ziekenhuis Gent
HEMODIALYSIS RESTORES ACTIVITY OF CYP3A4
Michaud et al, J Pharmacol Sci, 108: 157-163; 2008
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3434© 2008 Universitair Ziekenhuis Gent
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