Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport
Authors: Catherine K. Yeung, Danny D. Shen, Kenneth E. Thummel, Jonathan Himmelfarb
Journal: Kidney International (2013)

The pharmacokinetics of non-renally cleared drugs in patients with chronic kidney disease is often unpredictable. Some of this variability may be due to alterations in the expression and activity of extra renal drug-metabolizing enzymes and transporters, primarily localized in the liver and intestine. Studies conducted in rodent models of renal failure have shown decreased mRNA and protein expression of many members of the cytochrome P450 enzyme (CYP) gene family and the ATP-binding cassette (ABC) and solute carrier (SLC) gene families of drug transporters. Uremic toxins interfere with transcriptional activation, cause downregulation of gene expression mediated by proinflammatory cytokines, and directly inhibit the activity of the cytochrome P450s and drug transporters. While much has been learned about the effects of kidney disease on non-renal drug disposition, important questions remain regarding the mechanisms of these effects, as well as the interplay between drug-metabolizing enzymes and drug transporters in the uremic milieu. In this review, we have highlighted the existing gaps in our knowledge and understanding of the impact of chronic kidney disease on non-renal drug clearance, and identified areas of opportunity for future research. The pharmacokinetics of non-renally cleared drugs in patients with chronic kidney disease is often unpredictable. Some of this variability may be due to alterations in the expression and activity of extra renal drug-metabolizing enzymes and transporters, primarily localized in the liver and intestine. Studies conducted in rodent models of renal failure have shown decreased mRNA and protein expression of many members of the cytochrome P450 enzyme (CYP) gene family and the ATP-binding cassette (ABC) and solute carrier (SLC) gene families of drug transporters. Uremic toxins interfere with transcriptional activation, cause downregulation of gene expression mediated by proinflammatory cytokines, and directly inhibit the activity of the cytochrome P450s and drug transporters. While much has been learned about the effects of kidney disease on non-renal drug disposition, important questions remain regarding the mechanisms of these effects, as well as the interplay between drug-metabolizing enzymes and drug transporters in the uremic milieu. In this review, we have highlighted the existing gaps in our knowledge and understanding of the impact of chronic kidney disease on non-renal drug clearance, and identified areas of opportunity for future research. Chronic kidney disease (CKD) is a public health problem that affects >20 million people in the United States.1.Coresh J. Selvin E. Stevens L.A. et al.Prevalence of chronic kidney disease in the United States.JAMA. 2007; 298: 2038-2047Crossref PubMed Scopus (3894) Google Scholar Currently, almost 500,000 patients require chronic hemodialysis.2.MEDPAC A Data Book: healthcare spending and the Medicare program. 2009Google Scholar An average dialysis patient may require >12 medications.3.Manley H.J. Cannella C.A. Nondialysis (home) medication utilization and cost in diabetic and nondiabetic hemodialysis patients.Nephrol News Issues. 2005; 19: 27-28PubMed Google Scholar A pooled analysis identified 1593 medication-related problems in 385 dialysis patients, with overdosing or underdosing errors accounting for 20.4% of these issues.4.Manley H.J. Cannella C.A. Bailie G.R. et al.Medication-related problems in ambulatory hemodialysis patients: a pooled analysis.Am J Kidney Dis. 2005; 46: 669-680Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar Despite the large number of patients affected and the devastating consequences of medication-related problems, our understanding of the impact of kidney disease on drug disposition is incomplete, particularly for those drugs eliminated primarily by non-renal pathways. Obviously, clearance of drugs that depend primarily on the kidneys for elimination is reduced, but significant changes also occur in drug exposure with medications that are eliminated by the liver, intestine, and possibly other organs. In 2009, the Food and Drug Administration published a survey of New Drug Applications approved between January 2003 and July 2007 that assessed the impact of renal impairment on systemic exposure of new molecular entities.5.Zhang Y. Zhang L. Abraham S. et al.Assessment of the impact of renal impairment on systemic exposure of new molecular entities: evaluation of recent new drug applications.Clin Pharmacol Ther. 2009; 85: 305-311Crossref PubMed Scopus (125) Google Scholar In this analysis, New Drug Application sponsors for 37 orally administered drugs included renal impairment studies as part of their submission; 23 (62%) of these were eliminated by non-renal pathways (defined as the fraction eliminated via renal route <15). Despite being cleared non-renally, 13 of these 23 new drugs (57%) showed an average 1.5-fold increase in area under the plasma concentration–time curve (AUC) in renally impaired patients compared with healthy controls. In fact, the change in drug exposure for five drugs cleared mainly by hepatic metabolism and/or transport were of a magnitude (viz duloxetine ΔAUC +2.0-fold, tadalafil ΔAUC +2.7- to 4.1-fold, rosuvastatin ΔCplasma +3-fold, telithromycin ΔAUC +1.9-fold, solifenacin ΔAUC +2.1-fold) that required labeling recommendations for dose adjustment in renally impaired patients. Seven other drugs showed an effect of renal impairment on drug exposure but did not require dosage adjustment (aliskiren, alfuzosin, aprepitant, ranolazine, vardenafil, darifenacin, and lanthanum). These data along with a large body of earlier literature suggest that CKD alters the pharmacokinetics of drugs that are cleared by non-renal mechanisms; however, the underlying molecular mechanisms accounting for these pharmacokinetic changes remain poorly defined (reviewed by Nolin, LeBlond and others).6.Dreisbach A.W. Lertora J.J. The effect of chronic renal failure on drug metabolism and transport.Expert Opin Drug Metab Toxicol. 2008; 4: 1065-1074Crossref PubMed Scopus (178) Google Scholar, 7.Naud J. Nolin T.D. Leblond F.A. et al.Current understanding of drug disposition in kidney disease.J Clin Pharmacol. 2012; 52: 10S-22SCrossref PubMed Scopus (67) Google Scholar, 8.Nolin T.D. Frye R.F. Le P. et al.ESRD impairs nonrenal clearance of fexofenadine but not midazolam.J Am Soc Nephrol. 2009; 20: 2269-2276Crossref PubMed Scopus (105) Google Scholar, 9.Sun H. Huang Y. Frassetto L. et al.Effects of uremic toxins on hepatic uptake and metabolism of erythromycin.Drug Metab Dispos. 2004; 32: 1239-1246Crossref PubMed Scopus (113) Google Scholar The purpose of the present mini review is to highlight the present gaps in our understanding of the impact of CKD on non-renal drug clearance involving metabolism and transport processes and to identify areas of opportunity for future research. The following is a brief introduction to the key drug-metabolizing enzymes and drug transporters whose function is known to be altered in CKD. Phase I drug metabolism, involving oxidation, reduction, and hydrolysis, generally converts drug molecules to more polar or water-soluble metabolites that are readily excreted by the kidneys or via the biliary system. Drug oxidation, which is particularly known to be altered in CKD, is catalyzed by two large families of enzymes, namely the cytochrome P450 (CYPs) and flavin-containing monoxygenases (FMOs).10.Bauer L.A. Clinical pharmacokinetics and pharmacodynamics.in: DiPiro J.T. Talbert R.L. Yee G.C. Pharmacotherapy: A Pathophysiologic Approach. 6th edn. McGraw-Hill, New York2005: 51-73Google Scholar Many of the CYPs exhibit genetic polymorphisms that range from gene duplication resulting in gene overexpression to null mutations producing a nonfunctional enzyme. The recent focus of CYP research is on enzymes expressed in the liver and the intestinal mucosa, which govern the oral bioavailability (i.e., first-pass metabolism) and systemic metabolic clearance of drug molecules. Human hepatic CYPs include CYP3A4 and 3A5 (40% of total liver P450 content), CYP2Cs (25%), CYP1A2 (18%), CYP2E1 (9%), CYP2A6 (2%), CYP2D6 (2%), and CYP2B6 (<1%), as well as FMO3. Human intestinal CYPs that are functionally important include CYP1A1, CYP3A4, CYP3A5, and CYP2J2.11.Paine M.F. Hart H.L. Ludington S.S. et al.The human intestinal cytochrome P450 "pie".Drug Metab Dispos. 2006; 34: 880-886Crossref PubMed Scopus (698) Google Scholar CYP1A1, CYP1A2, CYP3A5, CYP4A1, and FMO1 are also expressed in human kidneys, but at levels much lower than those in the liver and intestine.11.Paine M.F. Hart H.L. Ludington S.S. et al.The human intestinal cytochrome P450 "pie".Drug Metab Dispos. 2006; 34: 880-886Crossref PubMed Scopus (698) Google Scholar, 12.Yeung C.K. Lang D.H. Thummel K.E. et al.Immunoquantitation of FMO1 in human liver, kidney, and intestine.Drug Metab Dispos. 2000; 28: 1107-1111PubMed Google Scholar Many drugs or their phase I metabolites also undergo conjugation reactions mediated by phase II enzymes.10.Bauer L.A. Clinical pharmacokinetics and pharmacodynamics.in: DiPiro J.T. Talbert R.L. Yee G.C. Pharmacotherapy: A Pathophysiologic Approach. 6th edn. McGraw-Hill, New York2005: 51-73Google Scholar In particular, N-acetylation and O-glucuronidation of drugs or drug metabolites are known to be altered in CKD.13.Nolin T.D. Naud J. Leblond F.A. et al.Emerging evidence of the impact of kidney disease on drug metabolism and transport.Clin Pharmacol Ther. 2008; 83: 898-903Crossref PubMed Scopus (199) Google Scholar The liver and intestinal mucosa are the major sites for the biotransformation of drugs and drug metabolites by phase II enzymes (Figure 1). It should be noted that the products of phase I and phase II metabolism are not always pharmacologically inactive or less toxic than the parent drug. Drug transporters also have a critical role in controlling drug exposure. Transporters are transmembrane proteins facilitating the passage of both drugs and other xenobiotics across biological barriers encountered during drug absorption, tissue distribution, and excretion. Transporters, such as drug-metabolizing enzymes, are expressed differentially across body tissues and are characterized as either uptake or influx transporters (transport into the cellular barrier) or efflux transporters (transport out of the cellular barrier). The importance of transporters in governing the intestinal absorption of drugs and nutrients and renal tubular secretion or reabsorption of drugs or their metabolites is increasingly being recognized. On the other hand, the role of hepatic sinusoidal transporters in regulating the access of drug substrates to the hepatocellular enzymes and that of canalicular transporters in biliary excretion of drugs and/or their conjugate metabolites are not as widely appreciated. Recent studies in experimental models of CKD have demonstrated altered expression and/or activities of intestinal and hepatic drug transporters that could modulate the respective intestinal absorption and hepatic uptake and metabolism of drugs.7.Naud J. Nolin T.D. Leblond F.A. et al.Current understanding of drug disposition in kidney disease.J Clin Pharmacol. 2012; 52: 10S-22SCrossref PubMed Scopus (67) Google Scholar, 14.Dreisbach A.W. The influence of chronic renal failure on drug metabolism and transport.Clin Pharmacol Ther. 2009; 86: 553-556Crossref PubMed Scopus (71) Google Scholar, 15.Sun H. Frassetto L. Benet L.Z. Effects of renal failure on drug transport and metabolism.Pharmacol Ther. 2006; 109: 1-11Crossref PubMed Scopus (223) Google Scholar More than 75 commonly used drugs have been reported to exhibit altered non-renal clearance in patients with CKD (see Table 1 for compilation). Most of these drugs are eliminated by CYP-mediated, oxidative metabolism (summarized in Figure 2). Only a few are subject to primary phase II metabolism, namely O-glucuronidation (diacerein, morphine, oxprenolol, and zidovudine) and N-acetylation (isoniazid and procainamide). In almost all cases, reduced non-renal clearance, along with an increase in oral bioavailability in some cases (especially for drugs that undergo first-pass metabolism in the intestinal mucosa and/or liver), was observed in CKD. A case in point is the diminished non-renal clearance of nimodipine, which could result in as much as a 7-fold increase in its AUC,16.Kirch W. Ramsch K.D. Duhrsen U. et al.Clinical pharmacokinetics of nimodipine in normal and impaired renal function.Int J Clin Pharmacol Res. 1984; 4: 381-384PubMed Google Scholar although the increase in drug exposure is usually more modest (1.5–3.0-fold), variable across patients, and dependent upon the degree of renal impairment and the dialysis regimen in patients near or at the end stage of renal disease. Increased clearance has been reported for a handful of drugs, including phenytoin, fosinopril, cefpiramide, nifedipine, bumetanide, and sulfadimidine.17.Dreisbach A.W. Lertora J.J. The effect of chronic renal failure on hepatic drug metabolism and drug disposition.Semin Dial. 2003; 16: 45-50Crossref PubMed Scopus (88) Google Scholar, 18.Elston A.C. Bayliss M.K. Park G.R. Effect of renal failure on drug metabolism by the liver.Br J Anaesth. 1993; 71: 282-290Crossref PubMed Scopus (82) Google Scholar At least in the case of phenytoin, the apparent acceleration in non-renal clearance is attributed to reduced binding of phenytoin to albumin in uremic serum, resulting in a higher fraction of circulating drug being available for uptake and metabolism by the liver.Table 1Currently used drugs reported to exhibit reduced non-renal clearance and/or increased oral bioavailability in CKD patientsaExcept where noted, nearly all the listed drugs undergo oxidative metabolism mediated by CYPs.AcyclovirDihydrocodeinedDrugs that mainly undergo N-acetylation.,cDrugs that mainly undergo O-glucuronidation.NortriptylineAliskirenDesmethyldiazepamOxprenololbDrugs known to exhibit an increase in oral bioavailability, as well as a reduced non-renal clearance.,cDrugs that mainly undergo O-glucuronidation.AlfuzosinDuloxetineProcainamidedDrugs that mainly undergo N-acetylation.AprepitantEncainidePropoxyphenebDrugs known to exhibit an increase in oral bioavailability, as well as a reduced non-renal clearance.AztreonamEprosartanPropranololbDrugs known to exhibit an increase in oral bioavailability, as well as a reduced non-renal clearance.BupropionErythromycinbDrugs known to exhibit an increase in oral bioavailability, as well as a reduced non-renal clearance.QuinaprilCaptoprilFelbamateRaloxifeneCapsofungin5-FluorouracilRanolazineCarvedilolGuanadrelReboxetineCefepimeImipenemRepaglinideCefmenoximeIsoniaziddDrugs that mainly undergo N-acetylation.RosuvastatinCefmetazoleKetoprofenRoxithromycinCefonicidKetorolacSimvastatinCefotaximeLanthanumSolifenacinCeftibutenLidocaineSparfloxacinCeftizoximeLomefloxacinTacrolimusCefsulodinLosartanTadalafilCeftriaxoneLovastatinTelithromycinCibenzolinMetoclopromideValsartanCilastatinMinoxidilVancomycinCimetidineMorphinecDrugs that mainly undergo O-glucuronidation.VardenafilCiprofloxaxinMoxalactamVerapamilbDrugs known to exhibit an increase in oral bioavailability, as well as a reduced non-renal clearance.CyclophophamideNefopamWarfarinDarifenacinNicardipinebDrugs known to exhibit an increase in oral bioavailability, as well as a reduced non-renal clearance.ZidovudinecDrugs that mainly undergo O-glucuronidation.DiacereincDrugs that mainly undergo O-glucuronidation.NimodipineDidanosineNitrendipineAbbreviations: CKD, chronic kidney disease; CYP, cytochrome P450.Modified and updated from Nolin13.Nolin T.D. Naud J. Leblond F.A. et al.Emerging evidence of the impact of kidney disease on drug metabolism and transport.Clin Pharmacol Ther. 2008; 83: 898-903Crossref PubMed Scopus (199) Google Scholar and Dreisbach and Lertora6.Dreisbach A.W. Lertora J.J. The effect of chronic renal failure on drug metabolism and transport.Expert Opin Drug Metab Toxicol. 2008; 4: 1065-1074Crossref PubMed Scopus (178) Google Scholar:a Except where noted, nearly all the listed drugs undergo oxidative metabolism mediated by CYPs.b Drugs known to exhibit an increase in oral bioavailability, as well as a reduced non-renal clearance.c Drugs that mainly undergo O-glucuronidation.d Drugs that mainly undergo N-acetylation. Open table in a new tab Abbreviations: CKD, chronic kidney disease; CYP, cytochrome P450. Modified and updated from Nolin13.Nolin T.D. Naud J. Leblond F.A. et al.Emerging evidence of the impact of kidney disease on drug metabolism and transport.Clin Pharmacol Ther. 2008; 83: 898-903Crossref PubMed Scopus (199) Google Scholar and Dreisbach and Lertora6.Dreisbach A.W. Lertora J.J. The effect of chronic renal failure on drug metabolism and transport.Expert Opin Drug Metab Toxicol. 2008; 4: 1065-1074Crossref PubMed Scopus (178) Google Scholar: A number of mechanisms have been hypothesized for the impairment of drug metabolism in CKD, particularly metabolic pathways mediated by CYP enzymes. The supporting evidence is drawn largely from experimental studies in animal models of acute and chronic renal failure. The proposed mechanisms include the following: alterations in gene transcription and protein translation, reduced CYP expression due to inhibition of hemoprotein biosynthesis and/or increased enzyme degradation, depletion of cofactors (e.g., supply of nicotinamide adenine dinucleotide phosphate (NADPH)), and direct competitive inhibition of CYP enzyme by circulating uremic constituents.13.Nolin T.D. Naud J. Leblond F.A. et al.Emerging evidence of the impact of kidney disease on drug metabolism and transport.Clin Pharmacol Ther. 2008; 83: 898-903Crossref PubMed Scopus (199) Google Scholar, 18.Elston A.C. Bayliss M.K. Park G.R. Effect of renal failure on drug metabolism by the liver.Br J Anaesth. 1993; 71: 282-290Crossref PubMed Scopus (82) Google Scholar Supply of δ-aminolevulinic acid is recognized as a rate-limiting step in the hepatic synthesis of CYP hemoproteins. Total microsomal CYP content is consistently reduced in various experimental models of renal failure, and mitochondrial δ-aminolevulinic synthetase activity is depressed in the two-step 5/6th nephrectomy model in rats.19.Uchida N. Kurata N. Shimada K. et al.Changes of hepatic microsomal oxidative drug metabolizing enzymes in chronic renal failure (CRF) rats by partial nephrectomy.Jpn J Pharmacol. 1995; 68: 431-439Crossref PubMed Scopus (36) Google Scholar Leber et al.20.Leber H.W. Schutterle G. Oxidative drug metabolism in liver microsomes from uremic rats.Kidney Int. 1972; 2: 152-158Abstract Full Text PDF PubMed Scopus (43) Google Scholar reported that intraperitoneal supplementation of δ-aminolevulinic acid in rats after subtotal nephrectomy normalized the level of CYP in the liver, but it did not reverse the reduction in CYP activities; hence, interference of hemoprotein synthesis is not a major mechanism of uremia's effect on CYP functioning in the rat. In addition, there is no experimental evidence in support of a diminished pool of hepatic NADPH/NADH+ in renal failure, thereby limiting microsomal oxidation reactions. Currently, the two most likely mechanisms are transcriptional and/or translational modifications and direct competitive inhibition of the CYP enzymes. Nolin et al.13.Nolin T.D. Naud J. Leblond F.A. et al.Emerging evidence of the impact of kidney disease on drug metabolism and transport.Clin Pharmacol Ther. 2008; 83: 898-903Crossref PubMed Scopus (199) Google Scholar have provided a thorough summary of experimental studies conducted over the past decade, which clearly demonstrated reduced expression of CYP genes and gene products (i.e., reduced mRNA and protein, or reduced protein with no change in mRNA) in several animal models of CKD. The precise mechanism(s) of the downregulation of CYP genes in these CKD models remains unknown. In addition, there is no prima facie evidence that transcriptional and/or translational modifications in CYP genes involved in drug metabolism occur in humans with CKD. The only available human data come from ex vivo studies of uremic serum obtained from patients with end-stage renal disease (ESRD),21.Guevin C. Michaud J. Naud J. et al.Down-regulation of hepatic cytochrome p450 in chronic renal failure: role of uremic mediators.Br J Pharmacol. 2002; 137: 1039-1046Crossref PubMed Scopus (89) Google Scholar, 22.Michaud J. Dube P. Naud J. et al.Effects of serum from patients with chronic renal failure on rat hepatic cytochrome P450.Br J Pharmacol. 2005; 144: 1067-1077Crossref PubMed Scopus (93) Google Scholar, 23.Michaud J. Nolin T.D. Naud J. et al.Effect of hemodialysis on hepatic cytochrome P450 functional expression.J Pharmacol Sci. 2008; 108: 157-163Crossref PubMed Scopus (62) Google Scholar which showed that incubating rat hepatocytes in primary culture with uremic human serum led to a decrease in protein expression and activity for all the major xenobiotic-metabolizing CYPs (i.e., 1A, 2C, 2D, 3A, and 4A families), except for CYP2E1. Michaud et al.23.Michaud J. Nolin T.D. Naud J. et al.Effect of hemodialysis on hepatic cytochrome P450 functional expression.J Pharmacol Sci. 2008; 108: 157-163Crossref PubMed Scopus (62) Google Scholar observed that, although pre-hemodialysis serum caused significant reductions in CYP protein expression compared with serum from healthy controls, post-dialysis serum showed no effect. Fractionation of uremic serum by ultrafiltration and size-exclusion high-performance liquid chromatography revealed that the inhibitory constituents have a molecular weight range between 10 and 15kDa. These investigators postulated that proinflammatory cytokines and parathyroid hormone, which have the requisite molecular size and are known to be elevated in CKD,24.Miyamoto T. Carrero J.J. Stenvinkel P. Inflammation as a risk factor and target for therapy in chronic kidney disease.Curr Opin Nephrol Hypertens. 2011; 20: 662-668Crossref PubMed Scopus (100) Google Scholar could mediate the downregulation of CYPs in CKD.25.Nolin T.D. Altered nonrenal drug clearance in ESRD.Curr Opin Nephrol Hypertens. 2008; 17: 555-559Crossref PubMed Scopus (52) Google Scholar, 26.Pichette V. Leblond F.A. Drug metabolism in chronic renal failure.Curr Drug Metab. 2003; 4: 91-103Crossref PubMed Scopus (97) Google Scholar Indeed, a follow-up study by the same group provided strong evidence that parathyroid hormone was a major component in uremic rat serum responsible for CYP downregulation, and parathyroidectomy abolished the alteration in CYP transcription and translation.27.Michaud J. Naud J. Chouinard J. et al.Role of parathyroid hormone in the downregulation of liver cytochrome P450 in chronic renal failure.J Am Soc Nephrol. 2006; 17: 3041-3048Crossref PubMed Scopus (58) Google Scholar Possible mechanisms of parathyroid hormone's effect on CYP gene regulation include increased cyclic adenosine monophosphate production, elevations in intracellular calcium, and/or activation of the nuclear factor-κBβ pathway. Downregulation of CYP gene expression in response to proinflammatory cytokines and other mediators of acute phase response (e.g., interleukin-1, interleukin-6, tumor necrosis factor-α, and interferon) are well established.28.Morgan E.T. Goralski K.B. Piquette-Miller M. et al.Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer.Drug Metab Dispos. 2008; 36: 205-216Crossref PubMed Scopus (317) Google Scholar It is also possible that circulating uremic constituents interfere with signaling of nuclear receptors involved in transcriptional activation of CYP genes, such as pregnane-X-receptor and constitutive androstane receptor. In addition, uremic plasma ultrafiltrate and peritoneal dialysate have been shown to inhibit vitamin D receptor–retinoid X receptor heterodimerization and attenuate activation of vitamin D-responsive genes, which include CYP3A4.29.Schmiedlin-Ren P. Thummel K.E. Fisher J.M. et al.Induction of CYP3A4 by 1 alpha,25-dihydroxyvitamin D3 is human cell line-specific and is unlikely to involve pregnane X receptor.Drug Metab Dispos. 2001; 29: 1446-1453PubMed Google Scholar, 30.Toell A. Degenhardt S. Grabensee B. et al.Inhibitory effect of uremic solutions on protein-DNA-complex formation of the vitamin D receptor and other members of the nuclear receptor superfamily.J Cell Biochem. 1999; 74: 386-394Crossref PubMed Scopus (10) Google Scholar The ex vivo evidence for uremia-induced transcriptional and translational modifications appears convincing, but there are caveats. Interspecies differences exist in the binding and activation of nuclear receptors (e.g., pregnane-X-receptor) that regulate the transcription of CYP genes, particularly between rodents and humans.31.Jones S.A. Moore L.B. Shenk J.L. et al.The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution.Mol Endocrinol. 2000; 14: 27-39Crossref PubMed Scopus (543) Google Scholar In addition, the human orthologs of rat CYP enzymes often have vastly different drug substrate selectivity.32.Bogaards J.J. Bertrand M. Jackson P. et al.Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man.Xenobiotica. 2000; 30: 1131-1152Crossref PubMed Scopus (311) Google Scholar The degree of uremia in animal models often exceeds that observed in stage III CKD subjects and may not be generalizable to this population; however, it may mimic the uremic state observed in patients with stage IV CKD or in suboptimally dialyzed stage V subjects. Hence, caution should be exercised in extrapolating genomic and functional data gathered from studies with rat hepatocytes and severely uremic animal models to the clinical context in CKD patients. It would be of considerable interest to repeat the ex vivo studies of uremic human serum on short-term CYP regulation using a three-dimensional human hepatocyte culture system (vide infra). The presence of circulating, competitive inhibitor(s) of CYP enzymes in uremic blood or plasma was demonstrated in some of the early experimental studies.6.Dreisbach A.W. Lertora J.J. The effect of chronic renal failure on drug metabolism and transport.Expert Opin Drug Metab Toxicol. 2008; 4: 1065-1074Crossref PubMed Scopus (178) Google Scholar, 33.Nolin T.D. Frye R.F. Matzke G.R. Hepatic drug metabolism and transport in patients with kidney disease.Am J Kidney Dis. 2003; 42: 906-925Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar As early as 1985, Terao et al.34.Terao N. Shen D.D. Reduced extraction of I-propranolol by perfused rat liver in the presence of uremic blood.J Pharmacol Exp Ther. 1985; 233: 277-284PubMed Google Scholar showed a reduced extraction of S-propranolol—a high intrinsic clearance CYP substrate—by livers isolated from normal rats perfused with uremic blood. Furthermore, livers from acute renal failure rats showed no reduction in S-propranolol extraction when perfused with normal blood from control rats. This set of cross-perfusion experiments presented the first evidence of a rapidly acting inhibitory factor(s) in uremic blood directly affecting the functioning of hepatic CYP enzymes. A later study by the same laboratory showed that a low-molecular-weight ultrafiltrate fraction (<10kDa) of uremic plasma obtained from ESRD patients was capable of inhibiting the oxidative metabolism of S-propranolol in human liver microsomes mediated by CYP2D6 and CYP1A2.35.Roskos L.K. Inhibition of the hepatic metabolism of (S)-propranolol by uremic blood constituents. Ph.D. thesis. University of Washington, Seattle1994Google Scholar Corroborating evidence of circulating uremic inhibitors have also been provided by Yoshitani et al.36.Yoshitani T. Yagi H. Inotsume N. et al.Effect of experimental renal failure on the pharmacokinetics of losartan in rats.Biol Pharm Bull. 2002; 25: 1077-1083Crossref PubMed Scopus (38) Google Scholar who showed that uremic sera from experimental models of acute renal failure in rats were capable of inhibiting oxidative metabolism of losartan in rat liver microsomes. Similarly, Taburet et al.37.Taburet A.M. Vincent I. Perello L. et al.Impairment of drug biotransformation in renal disease: An in vitro model.Clin Pharmacol Ther. 1996; 59: 136Crossref Google Scholar reported that uremic plasma from ESRD patients inhibited the metabolism of the CYP2C9 probe tolbutamide and the CYP3A probe midazolam in human liver microsomes from donors with normal renal function. Another piece of indirect evidence comes from pharmacokinetic studies in ESRD patients undergoing hemodialysis, where the metabolic clearance of both propranolol38.Bianchetti G. Graziani G. Brancaccio D. et al.Pharmacokinetics and effects of propranolol in terminal uraemic patients and in patients undergoing regular dialysis treatment.Clin Pharmacokinet. 1976; 1: 373-384Crossref PubMed Scopus (120) Google Scholar and telithromycin39.Shi J. Montay G. Chapel S. et al.Pharmacokinetics and safety of the ketolide telithromycin in patients with renal impairment.J Clin Pharmacol. 2004; 44: 234-244Crossref PubMed Scopus (37) Google Scholar after oral administration was partially or completely normalized when the drug was given shortly after a regular dialysis session compared with before dialysis. The rapid reversibility of uremia's effect is more consistent with dialytic removal of competitive enzyme inhibitors than reversal of uremia-induced downregulation of CYP. Although the latter process normally takes several days to achieve in accordance with the turnover half-life of CYPs (≥24h), downregulation in the expression of one or more CYP proteins cannot be completely excluded.40.Yang J. Liao M. Shou M. et al.Cytochrome p450 turno