Effects of uremic toxins on transport and metabolism of different biopharmaceutics drug disposition classification system xenobiotics.

Chronic kidney disease (CKD) is recognized to cause pharmacokinetic changes in renally excreted drugs; however, pharmacokinetic changes are also reported for drugs that are nonrenally eliminated. Few studies have investigated how uremic toxins may affect drug transporters and metabolizing enzymes and how these may result in pharmacokinetic/metabolic changes in CKD. Here, we investigated the effects of uremic toxins and human uremic serum on the transport of the prototypical transporter substrate [(3) H]-estrone sulfate and three Biopharmaceutics Drug Disposition Classification System (BDDCS) drugs, propranolol, losartan, and eprosartan. We observed a significant decrease in [(3) H]-estrone sulfate, losartan, and eprosartan uptake with some uremic toxins in both transfected cells and rat hepatocytes. The uptake of losartan was decreased in rat and human hepatocytes (28% and 48%, respectively) in the presence of hemodialysis (HD) serum. Time-course studies of losartan showed a 27%, 65%, and 68% increase in area under the curve (AUC) in the presence of HD serum, rifampin, and sulfaphenazole, respectively. Intracellular losartan AUC decreased significantly in the treatment groups, and the metabolite AUC decreased by 41% and 26% in rifampin- and sulfaphenazole-treated group, respectively. The intracellular AUC of eprosartan increased 190% in the presence of HD serum. These studies indicate that the uremic toxins contained in HD serum play an important role in drug disposition through drug transporters, and that there would be differential effects depending on the BDDCS classification of the drug.

[1]  F. Leblond,et al.  Drug metabolism in chronic renal failure. , 2003, Current drug metabolism.

[2]  L. Benet,et al.  IN VITRO AND IN VIVO CORRELATION OF HEPATIC TRANSPORTER EFFECTS ON ERYTHROMYCIN METABOLISM: CHARACTERIZING THE IMPORTANCE OF TRANSPORTER-ENZYME INTERPLAY , 2006, Drug Metabolism and Disposition.

[3]  Y. Sawada,et al.  Effects of Uremic Serum and Uremic Toxins on Hepatic Uptake of Digoxin , 2008, Therapeutic drug monitoring.

[4]  T. Nolin.  Altered nonrenal drug clearance in ESRD , 2008, Current opinion in nephrology and hypertension.

[5]  D. Jorkasky,et al.  Pharmacokinetics and Protein Binding of Eprosartan in Healthy Volunteers and in Patients with Varying Degrees of Renal Impairment , 1998, Journal of clinical pharmacology.

[6]  Hong Sun,et al.  EFFECTS OF UREMIC TOXINS ON HEPATIC UPTAKE AND METABOLISM OF ERYTHROMYCIN , 2004, Drug Metabolism and Disposition.

[7]  F. Leblond,et al.  Down‐regulation of hepatic cytochrome P450 in chronic renal failure: role of uremic mediators , 2002, British journal of pharmacology.

[8]  M. Niemi,et al.  Influence of Drug Transporter Polymorphisms on Pravastatin Pharmacokinetics in Humans , 2007, Pharmaceutical Research.

[9]  R. Kim,et al.  Hepatic drug transporters, old and new: Pharmacogenomics, drug response, and clinical relevance , 2009, Hepatology.

[10]  D. Rosskopf,et al.  Disposition of ezetimibe is influenced by polymorphisms of the hepatic uptake carrier OATP1B1 , 2008, Pharmacogenetics and genomics.

[11]  L. Benet,et al.  Metabolism of digoxin and digoxigenin digitoxosides in rat liver microsomes: involvement of cytochrome P4503A. , 1999, Xenobiotica; the fate of foreign compounds in biological systems.

[12]  A. Dreisbach,et al.  The Effect of Chronic Renal Failure on Hepatic Drug Metabolism and Drug Disposition , 2003, Seminars in dialysis.

[13]  Leslie Z Benet,et al.  Multiple Transporters Affect the Disposition of Atorvastatin and Its Two Active Hydroxy Metabolites: Application of in Vitro and ex Situ Systems , 2006, Journal of Pharmacology and Experimental Therapeutics.

[14]  C. Xia,et al.  INVESTIGATION OF DRUG-DRUG INTERACTION POTENTIAL OF BORTEZOMIB IN VIVO IN FEMALE SPRAGUE-DAWLEY RATS AND IN VITRO IN HUMAN LIVER MICROSOMES , 2006, Drug Metabolism and Disposition.

[15]  K. Winters,et al.  Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end‐stage renal disease , 2009, Journal of clinical pharmacy and therapeutics.

[16]  Y. Sugiyama,et al.  Function of uptake transporters for taurocholate and estradiol 17beta-D-glucuronide in cryopreserved human hepatocytes. , 2003, Drug metabolism and pharmacokinetics.

[17]  Leslie Z. Benet,et al.  The Role of Transporters in the Pharmacokinetics of Orally Administered Drugs , 2009, Pharmaceutical Research.

[18]  Raymond Vanholder,et al.  Review on uremic toxins: classification, concentration, and interindividual variability. , 2003, Kidney international.

[19]  H. Takanaga,et al.  Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney. , 2002, Kidney international.

[20]  Y. Sugiyama,et al.  Recent Advances in Carrier-mediated Hepatic Uptake and Biliary Excretion of Xenobiotics , 1996, Pharmaceutical Research.

[21]  K. Brouwer,et al.  Relationship between Drug/Metabolite Exposure and Impairment of Excretory Transport Function , 2009, Drug Metabolism and Disposition.

[22]  T. Nolin,et al.  Emerging Evidence of the Impact of Kidney Disease on Drug Metabolism and Transport , 2008, Clinical pharmacology and therapeutics.

[23]  F. Leblond,et al.  Downregulation of hepatic cytochrome P450 in chronic renal failure. , 2001, Journal of the American Society of Nephrology : JASN.

[24]  T. Nolin,et al.  ESRD impairs nonrenal clearance of fexofenadine but not midazolam. , 2009, Journal of the American Society of Nephrology : JASN.

[25]  Leslie Z. Benet,et al.  Predicting Drug Disposition via Application of BCS: Transport/Absorption/ Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System , 2004, Pharmaceutical Research.

[26]  L. Zhang,et al.  Assessment of the Impact of Renal Impairment on Systemic Exposure of New Molecular Entities: Evaluation of Recent New Drug Applications , 2009, Clinical pharmacology and therapeutics.

[27]  L. Benet,et al.  Elucidating Rifampin's Inducing and Inhibiting Effects on Glyburide Pharmacokinetics and Blood Glucose in Healthy Volunteers: Unmasking the Differential Effects of Enzyme Induction and Transporter Inhibition for a Drug and Its Primary Metabolite , 2009, Clinical pharmacology and therapeutics.

[28]  C. Paulos,et al.  The pharmacokinetics of nifurtimox in chronic renal failure , 2004, European Journal of Clinical Pharmacology.

[29]  M. Schuler,et al.  Pharmacokinetics of sorafenib in patients with renal impairment undergoing hemodialysis. , 2009, International journal of clinical pharmacology and therapeutics.

[30]  A. Sparreboom,et al.  Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination , 2005, Expert opinion on drug metabolism & toxicology.

[31]  T. Nolin,et al.  Effect of hemodialysis on hepatic cytochrome P450 functional expression. , 2008, Journal of pharmacological sciences.

[32]  Leslie Z. Benet,et al.  Ex Situ Inhibition of Hepatic Uptake and Efflux Significantly Changes Metabolism: Hepatic Enzyme-Transporter Interplay , 2004, Journal of Pharmacology and Experimental Therapeutics.

[33]  L. Benet,et al.  Hepatic Clearance, but Not Gut Availability, of Erythromycin Is Altered in Patients With End‐Stage Renal Disease , 2010, Clinical pharmacology and therapeutics.

[34]  F. Leblond,et al.  Effects of serum from patients with chronic renal failure on rat hepatic cytochrome P450 , 2005, British journal of pharmacology.