© 2008 universitair ziekenhuis gent pharmacokinetics in ckd r vanholder university hospital, gent,...

© 2008 Universitair Ziekenhuis Gent

PHARMACOKINETICS IN CKD

R Vanholder

University Hospital, Gent,

Belgium

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


CONTRIBUTORS TO PHARMACOKINETICS IN CKD

Renal clearanceGlomerulus

Tubulus

MetabolismEnterocyte

Hepatocyte

Excretion in intestineDirect

Biliary

Protein binding

Distribution volume

Disturbed gastro-intestinal motility and uptake


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


RENAL CLEARANCE


drug


ORGANIC ANION TRANSPORTERS


OAT ACTIVITY IS DEPRESSED IN KIDNEY FAILURE

Takeuchi, KI, 60: 1058-1068; 2001


UREMIC TOXINS INHIBIT OATs

Wang and Sweet, Biochem Pharmacol, 84: 1088-1095; 2012


NON-RENAL CLEARANCE


METABOLIC ACTIVITY CYPs IS DECREASED IN CKD

Leblond at al, JASN, 13: 1579–1585; 2002


PROTEIN BINDING


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


IMPORTANCE OF PROTEIN BINDING

Vanholder et al, KI, 33: 996-1004; 1989

1717© 2008 Universitair Ziekenhuis Gent Vanholder et al, KI, 33: 996-1004; 1989

IMPORTANCE OF PROTEIN BINDING


OTHER COMPETITORS

Indoxyl sulfate

Indole-acetic acid

P-cresylsulfate

…


PRACTICAL CONSEQUENCES


DISTRIBUTION VOLUME


Vd C0

Dose X0 IV

DISTRIBUTION VOLUME


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.


INTESTINAL ABSORPTION


INTESTINAL MOBILITY IS DECREASED IN DIABETES

Rana et al, Diab Tech Ther, 13: 1115-1120; 2011


INTESTINAL MOBILITY IS DECREASED IN CKD

Strid et al, Digestion, 13: 129-137; 2003


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


ABSORPTION OF MYCOPHENOLATE MOFETYL BY SEVELAMER

Pieper et al, NDT, 19: 2630-2633; 2004


THE EFFECT OF DIALYSIS


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)


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


HEMODIALYSIS RESTORES ACTIVITY OF CYP3A4

Michaud et al, J Pharmacol Sci, 108: 157-163; 2008


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

© 2008 universitair ziekenhuis gent pharmacokinetics in ckd r vanholder university hospital, gent,...

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