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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 2 2 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 3 3 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 4 4 RENAL CLEARANCE © 2008 Universitair Ziekenhuis Gent © 2008 Universitair Ziekenhuis Gent 6 6 drug © 2008 Universitair Ziekenhuis Gent 7 7 © 2008 Universitair Ziekenhuis Gent 8 8 ORGANIC ANION TRANSPORTERS © 2008 Universitair Ziekenhuis Gent 9 9 OAT ACTIVITY IS DEPRESSED IN KIDNEY FAILURE © 2008 Universitair Ziekenhuis Gent Takeuchi, KI, 60: 1058-1068; 2001 10 10 UREMIC TOXINS INHIBIT OATs © 2008 Universitair Ziekenhuis Gent Wang and Sweet, Biochem Pharmacol, 84: 1088-1095; 2012 11 11 NON-RENAL CLEARANCE © 2008 Universitair Ziekenhuis Gent METABOLIC ACTIVITY CYPs IS DECREASED IN CKD © 2008 Universitair Ziekenhuis Gent Leblond at al, JASN, 13: 1579–1585; 2002 13 13 PROTEIN BINDING © 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 © 2008 Universitair Ziekenhuis Gent 15 15 IMPORTANCE OF PROTEIN BINDING © 2008 Universitair Ziekenhuis Gent Vanholder et al, KI, 33: 996-1004; 1989 16 16 IMPORTANCE OF PROTEIN BINDING © 2008 Universitair Ziekenhuis Gent Vanholder et al, KI, 33: 996-1004; 1989 17 17 OTHER COMPETITORS Indoxyl sulfate Indole-acetic acid P-cresylsulfate … © 2008 Universitair Ziekenhuis Gent 18 18 PRACTICAL CONSEQUENCES © 2008 Universitair Ziekenhuis Gent 19 19 PRACTICAL CONSEQUENCES © 2008 Universitair Ziekenhuis Gent 20 20 PRACTICAL CONSEQUENCES © 2008 Universitair Ziekenhuis Gent 21 21 DISTRIBUTION VOLUME © 2008 Universitair Ziekenhuis Gent DISTRIBUTION VOLUME Dose X0 IV Vd C0 © 2008 Universitair Ziekenhuis Gent 23 23 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. © 2008 Universitair Ziekenhuis Gent 24 24 INTESTINAL ABSORPTION © 2008 Universitair Ziekenhuis Gent INTESTINAL MOBILITY IS DECREASED IN DIABETES © 2008 Universitair Ziekenhuis Gent Rana et al, Diab Tech Ther, 13: 1115-1120; 2011 26 26 INTESTINAL MOBILITY IS DECREASED IN CKD © 2008 Universitair Ziekenhuis Gent Strid et al, Digestion, 13: 129-137; 2003 27 27 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 © 2008 Universitair Ziekenhuis Gent 28 28 ABSORPTION OF MYCOPHENOLATE MOFETYL BY SEVELAMER © 2008 Universitair Ziekenhuis Gent Pieper et al, NDT, 19: 2630-2633; 2004 29 29 THE EFFECT OF DIALYSIS © 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) © 2008 Universitair Ziekenhuis Gent 31 31 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) © 2008 Universitair Ziekenhuis Gent 32 32 HEMODIALYSIS RESTORES ACTIVITY OF CYP3A4 © 2008 Universitair Ziekenhuis Gent Michaud et al, J Pharmacol Sci, 108: 157-163; 2008 33 33 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 34 34