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Consequences of Renal Failure on Non-Renal Clearance of Drugs

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Abstract

Kidney disease not only alters the renal elimination but also the non-renal disposition of drugs that are metabolized by the liver. Indeed, modifications in the expression and activity of intestinal and hepatic drug metabolism enzymes and uptake and efflux transporters have been reported. Accumulated uremic toxins, inflammatory cytokines, and parathyroid hormones may modulate these proteins either directly or by inhibiting gene expression. This can lead to important unintended variations in exposure and response when drugs are administered without dose adjustment for reduced renal function. This review summarizes our current understanding of non-renal clearance in circumstances of chronic and acute renal failure with experimental but also clinical studies. It also evaluates the clinical impact on drug disposition. Predicting the extent of the drug disposition modification is difficult first because of the complex interplay between metabolic enzymes and transport proteins but also because of the differential effects in the different organs (liver, intestines). Recommendations of the US FDA are presented as they may be potentially helpful tools to predict these modifications when no specific pharmacokinetic studies are available.

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References

  1. Zhang Q-L, Rothenbacher D. Prevalence of chronic kidney disease in population-based studies: systematic review. BMC Public Health. 2008;8:117.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Ishani A, et al. US Renal Data System 2013 annual data report. Am J Kidney Dis. 2014;63:A7.

    Article  PubMed  Google Scholar 

  3. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007;298:2038–47.

    Article  CAS  PubMed  Google Scholar 

  4. Reidenberg MM. The biotransformation of drugs in renal failure. Am J Med. 1977;62:482–5.

    Article  CAS  PubMed  Google Scholar 

  5. Marbury TC, Ruckle JL, Hatorp V, Andersen MP, Nielsen KK, Huang WC, et al. Pharmacokinetics of repaglinide in subjects with renal impairment. Clin Pharmacol Ther. 2000;67:7–15.

    Article  CAS  PubMed  Google Scholar 

  6. Muirhead GJ, Wilner K, Colburn W, Haug-Pihale G, Rouviex B. The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil. Br J Clin Pharmacol. 2002;53(Suppl 1):21S–30S.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Molander L, Hansson A, Lunell E, Alainentalo L, Hoffmann M, Larsson R. Pharmacokinetics of nicotine in kidney failure. Clin Pharmacol Ther. 2000;68:250–60.

    Article  CAS  PubMed  Google Scholar 

  8. Dreisbach AW, Lertora JJL. The effect of chronic renal failure on hepatic drug metabolism and drug disposition. Semin Dial. 2003;16:45–50.

    Article  PubMed  Google Scholar 

  9. Gibson TP. Renal disease and drug metabolism: an overview. Am J Kidney Dis. 1986;8:7–17.

    Article  CAS  PubMed  Google Scholar 

  10. Nolin TD, Frye RF, Matzke GR. Hepatic drug metabolism and transport in patients with kidney disease. Am J Kidney Dis. 2003;42:906–25.

    Article  CAS  PubMed  Google Scholar 

  11. Talbert RL. Drug dosing in renal insufficiency. J Clin Pharmacol. 1994;34:99–110.

    Article  CAS  PubMed  Google Scholar 

  12. Vanholder R, Van Landschoot N, De Smet R, Schoots A, Ringoir S. Drug protein binding in chronic renal failure: evaluation of nine drugs. Kidney Int. 1988;33:996–1004.

    Article  CAS  PubMed  Google Scholar 

  13. Lam YW, Banerji S, Hatfield C, Talbert RL. Principles of drug administration in renal insufficiency. Clin Pharmacokinet. 1997;32:30–57.

    Article  CAS  PubMed  Google Scholar 

  14. Elston AC, Bayliss MK, Park GR. Effect of renal failure on drug metabolism by the liver. Br J Anaesth. 1993;71:282–90.

    Article  CAS  PubMed  Google Scholar 

  15. Benet LZ, Hoener B. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther. 2002;71:115–21.

    Article  CAS  PubMed  Google Scholar 

  16. Leblond FA, Giroux L, Villeneuve JP, Pichette V. Decreased in vivo metabolism of drugs in chronic renal failure. Drug Metab Dispos. 2000;28:1317–20.

    CAS  PubMed  Google Scholar 

  17. Tanaka E, Breimer DD. In vivo function tests of hepatic drug-oxidizing capacity in patients with liver disease. J Clin Pharm Ther. 1997;22:237–49.

    Article  CAS  PubMed  Google Scholar 

  18. Leblond F, Guévin C, Demers C, Pellerin I, Gascon-Barré M, Pichette V. Downregulation of hepatic cytochrome P450 in chronic renal failure. J Am Soc Nephrol. 2001;12:326–32.

    CAS  PubMed  Google Scholar 

  19. Guévin C, Michaud J, Naud J, Leblond FA, Pichette V. Down-regulation of hepatic cytochrome p450 in chronic renal failure: role of uremic mediators. Br J Pharmacol. 2002;137:1039–46.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Leblond FA, Petrucci M, Dubé P, Bernier G, Bonnardeaux A, Pichette V. Downregulation of intestinal cytochrome p450 in chronic renal failure. J Am Soc Nephrol. 2002;13:1579–85.

    Article  CAS  PubMed  Google Scholar 

  21. Kanfer A, Stamatakis G, Torlotin JC, Fredj G, Kenouch S, Méry JP. Changes in erythromycin pharmacokinetics induced by renal failure. Clin Nephrol. 1987;27:147–50.

    CAS  PubMed  Google Scholar 

  22. Bianchetti G, Graziani G, Brancaccio D, Morganti A, Leonetti G, Manfrin M, et al. Pharmacokinetics and effects of propranolol in terminal uraemic patients and in patients undergoing regular dialysis treatment. Clin Pharmacokinet. 1976;1:373–84.

    Article  CAS  PubMed  Google Scholar 

  23. Zhou S-F, Liu J-P, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev. 2009;41:89–295.

    Article  CAS  PubMed  Google Scholar 

  24. Yiannakopoulou EC. Pharmacogenomics of phase II metabolizing enzymes and drug transporters: clinical implications. Pharmacogenomics J. 2013;13:105–9.

    Article  CAS  PubMed  Google Scholar 

  25. Kim YG, Shin JG, Shin SG, Jang IJ, Kim S, Lee JS, et al. Decreased acetylation of isoniazid in chronic renal failure. Clin Pharmacol Ther. 1993;54:612–20.

    Article  CAS  PubMed  Google Scholar 

  26. Kirwan CJ, MacPhee IAM, Lee T, Holt DW, Philips BJ. Acute kidney injury reduces the hepatic metabolism of midazolam in critically ill patients. Intensive Care Med. 2012;38:76–84.

    Article  CAS  PubMed  Google Scholar 

  27. Dowling TC, Briglia AE, Fink JC, Hanes DS, Light PD, Stackiewicz L, et al. Characterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease. Clin Pharmacol Ther. 2003;73:427–34.

    Article  CAS  PubMed  Google Scholar 

  28. Simard E, Naud J, Michaud J, Leblond FA, Bonnardeaux A, Guillemette C, et al. Downregulation of hepatic acetylation of drugs in chronic renal failure. J Am Soc Nephrol. 2008;19:1352–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Osborne R, Joel S, Grebenik K, Trew D, Slevin M. The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther. 1993;54:158–67.

    Article  CAS  PubMed  Google Scholar 

  30. Yu C, Ritter JK, Krieg RJ, Rege B, Karnes TH, Sarkar MA. Effect of chronic renal insufficiency on hepatic and renal udp-glucuronyltransferases in rats. Drug Metab Dispos. 2006;34:621–7.

    Article  CAS  PubMed  Google Scholar 

  31. Benet LZ, Cummins CL, Wu CY. Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data. Curr Drug Metab. 2003;4:393–8.

    Article  CAS  PubMed  Google Scholar 

  32. Lam JL, Okochi H, Huang Y, Benet LZ. In vitro and in vivo correlation of hepatic transporter effects on erythromycin metabolism: characterizing the importance of transporter-enzyme interplay. Drug Metab Dispos. 2006;34:1336–44.

    Article  CAS  PubMed  Google Scholar 

  33. Benet LZ, Cummins CL, Wu CY. Unmasking the dynamic interplay between efflux transporters and metabolic enzymes. Int J Pharm. 2004;277:3–9.

    Article  CAS  PubMed  Google Scholar 

  34. Ho RH, Kim RB. Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther. 2005;78:260–77.

    Article  CAS  PubMed  Google Scholar 

  35. Gehr TW, Sica DA, Slugg PH, Hammett JL, Raymond R, Ford NF. The pharmacokinetics of pravastatin in patients on chronic hemodialysis. Eur J Clin Pharmacol. 1997;53:117–21.

    Article  CAS  PubMed  Google Scholar 

  36. Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug transport and metabolism. Pharmacol Ther. 2006;109:1–11.

    Article  CAS  PubMed  Google Scholar 

  37. Tsujimoto M, Hatozaki D, Shima D, Yokota H, Furukubo T, Izumi S, et al. Influence of serum in hemodialysis patients on the expression of intestinal and hepatic transporters for the excretion of pravastatin. Ther Apher Dial. 2012;16:580–7.

    Article  CAS  PubMed  Google Scholar 

  38. Naud J, Michaud J, Boisvert C, Desbiens K, Leblond FA, Mitchell A, et al. Down-regulation of intestinal drug transporters in chronic renal failure in rats. J Pharmacol Exp Ther. 2007;320:978–85.

    Article  CAS  PubMed  Google Scholar 

  39. Okabe H, Hashimoto Y, Inui KI. Pharmacokinetics and bioavailability of tacrolimus in rats with experimental renal dysfunction. J Pharm Pharmacol. 2000;52:1467–72.

    Article  CAS  PubMed  Google Scholar 

  40. Laouari D, Yang R, Veau C, Blanke I, Friedlander G. Two apical multidrug transporters, P-gp and MRP2, are differently altered in chronic renal failure. Am J Physiol Renal Physiol. 2001;280:F636–45.

    CAS  PubMed  Google Scholar 

  41. Naud J, Michaud J, Leblond FA, Lefrancois S, Bonnardeaux A, Pichette V. Effects of chronic renal failure on liver drug transporters. Drug Metab Dispos. 2008;36:124–8.

    Article  CAS  PubMed  Google Scholar 

  42. Michaud J, Dubé P, Naud J, Leblond FA, Desbiens K, Bonnardeaux A, et al. Effects of serum from patients with chronic renal failure on rat hepatic cytochrome P450. Br J Pharmacol. 2005;144:1067–77.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Michaud J, Nolin TD, Naud J, Dani M, Lafrance J-P, Leblond FA, et al. Effect of hemodialysis on hepatic cytochrome P450 functional expression. J Pharmacol Sci. 2008;108:157–63.

    Article  CAS  PubMed  Google Scholar 

  44. Nolin TD, Appiah K, Kendrick SA, Le P, McMonagle E, Himmelfarb J. Hemodialysis acutely improves hepatic CYP3A4 metabolic activity. J Am Soc Nephrol. 2006;17:2363–7.

    Article  CAS  PubMed  Google Scholar 

  45. Terao N, Shen DD. Reduced extraction of I-propranolol by perfused rat liver in the presence of uremic blood. J Pharmacol Exp Ther. 1985;233:277–84.

    CAS  PubMed  Google Scholar 

  46. Michaud J, Naud J, Chouinard J, Désy F, Leblond FA, Desbiens K, et al. Role of parathyroid hormone in the downregulation of liver cytochrome P450 in chronic renal failure. J Am Soc Nephrol. 2006;17:3041–8.

    Article  CAS  PubMed  Google Scholar 

  47. Hanada K, Ogawa R, Son K, Sasaki Y, Kikkawa A, Ichihara S, et al. Effects of indoxylsulfate on the in vitro hepatic metabolism of various compounds using human liver microsomes and hepatocytes. Nephron Physiol. 2006;103:179–86.

    Article  Google Scholar 

  48. Masereeuw R, Terlouw SA, van Aubel RA, Russel FG, Miller DS. Endothelin B receptor-mediated regulation of ATP-driven drug secretion in renal proximal tubule. Mol Pharmacol. 2000;57:59–67.

    CAS  PubMed  Google Scholar 

  49. Nolin TD, Frye RF, Le P, Sadr H, Naud J, Leblond FA, et al. ESRD impairs nonrenal clearance of fexofenadine but not midazolam. J Am Soc Nephrol. 2009;20:2269–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Sun H, Huang Y, Frassetto L, Benet LZ. Effects of uremic toxins on hepatic uptake and metabolism of erythromycin. Drug Metab Dispos. 2004;32:1239–46.

    Article  CAS  PubMed  Google Scholar 

  51. Nolin TD, Naud J, Leblond FA, Pichette V. Emerging evidence of the impact of kidney disease on drug metabolism and transport. Clin Pharmacol Ther. 2008;83:898–903.

    Article  CAS  PubMed  Google Scholar 

  52. Nolin TD. Altered nonrenal drug clearance in ESRD. Curr Opin Nephrol Hypertens. 2008;17:555–9.

    Article  CAS  PubMed  Google Scholar 

  53. Mutsaers HAM, Wilmer MJG, Reijnders D, Jansen J, van den Broek PHH, Forkink M, et al. Uremic toxins inhibit renal metabolic capacity through interference with glucuronidation and mitochondrial respiration. Biochim Biophys Acta. 2013;1832:142–50.

    Article  CAS  PubMed  Google Scholar 

  54. Tsujimoto M, Nagano Y, Hosoda S, Shiraishi A, Miyoshi A, Hiraoka S, et al. Effects of decreased vitamin D and accumulated uremic toxin on human CYP3A4 activity in patients with end-stage renal disease. Toxins (Basel). 2013;5:1475–85.

    Article  CAS  PubMed Central  Google Scholar 

  55. Philips BJ, Lane K, Dixon J, Macphee I. The effects of acute renal failure on drug metabolism. Expert Opin Drug Metab Toxicol. 2014;10:11–23.

    Article  CAS  PubMed  Google Scholar 

  56. Vilay AM, Churchwell MD, Mueller BA. Clinical review: drug metabolism and nonrenal clearance in acute kidney injury. Crit Care. 2008;12:235.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Macias WL, Mueller BA, Scarim SK. Vancomycin pharmacokinetics in acute renal failure: preservation of nonrenal clearance. Clin Pharmacol Ther. 1991;50:688–94.

    Article  CAS  PubMed  Google Scholar 

  58. Mueller BA, Scarim SK, Macias WL. Comparison of imipenem pharmacokinetics in patients with acute or chronic renal failure treated with continuous hemofiltration. Am J Kidney Dis. 1993;21:172–9.

    Article  CAS  PubMed  Google Scholar 

  59. Yu SY, Chung HC, Kim EJ, Kim SH, Lee I, Kim SG, et al. Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of intravenous theophylline in rats: the role of CYP2E1 induction in 1,3-dimethyluric acid formation. J Pharm Pharmacol. 2002;54:1687–92.

    Article  CAS  PubMed  Google Scholar 

  60. Okabe H, Yano I, Hashimoto Y, Saito H, Inui K. Evaluation of increased bioavailability of tacrolimus in rats with experimental renal dysfunction. J Pharm Pharmacol. 2002;54:65–70.

    Article  CAS  PubMed  Google Scholar 

  61. Okabe H, Higashi T, Ohta T, Hashimoto Y. Intestinal absorption and hepatic extraction of propranolol and metoprolol in rats with bilateral ureteral ligation. Biol Pharm Bull. 2004;27:1422–7.

    Article  CAS  PubMed  Google Scholar 

  62. Lee YH, Lee MH, Shim CK. Decreased systemic clearance of diltiazem with increased hepatic metabolism in rats with uranyl nitrate-induced acute renal failure. Pharm Res. 1992;9:1599–606.

    Article  CAS  PubMed  Google Scholar 

  63. Choi JS, Lee JH, Burm JP. Pharmacokinetics of diltiazem and its major metabolite, deacetyidiltiazem after oral administration of diltiazem in mild and medium folate-induced renal failure rabbits. Arch Pharm Res. 2001;24:333–7.

    Article  CAS  PubMed  Google Scholar 

  64. Lee AK, Lee JH, Kwon JW, Kim WB, Kim SG, Kim SH, et al. Pharmacokinetics of clarithromycin in rats with acute renal failure induced by uranyl nitrate. Biopharm Drug Dispos. 2004;25:273–82.

    Article  CAS  PubMed  Google Scholar 

  65. Lee JH, Lee MG. Effects of acute renal failure on the pharmacokinetics of telithromycin in rats: negligible effects of increase in CYP3A1 on the metabolism of telithromycin. Biopharm Drug Dispos. 2007;28:157–66.

    Article  CAS  PubMed  Google Scholar 

  66. Kusaba J, Kajikawa N, Kawasaki H, Kurosaki Y, Aiba T. Comparative study on altered hepatic metabolism of CYP3A substrates in rats with glycerol-induced acute renal failure. Biopharm Drug Dispos. 2012;33:22–9.

    Article  CAS  PubMed  Google Scholar 

  67. Heinemeyer G, Gramm HJ, Roots I, Dennhardt R, Simgen W. The kinetics of metamizol and its metabolites in critical-care patients with acute renal dysfunction. Eur J Clin Pharmacol. 1993;45:445–50.

    Article  CAS  PubMed  Google Scholar 

  68. Huang ZH, Murakami T, Okochi A, Yumoto R, Nagai J, Takano M. Expression and function of P-glycoprotein in rats with glycerol-induced acute renal failure. Eur J Pharmacol. 2000;406:453–60.

    Article  CAS  PubMed  Google Scholar 

  69. Obialo CI, Okonofua EC, Nzerue MC, Tayade AS, Riley LJ. Role of hypoalbuminemia and hypocholesterolemia as copredictors of mortality in acute renal failure. Kidney Int. 1999;56:1058–63.

    Article  CAS  PubMed  Google Scholar 

  70. Naud J, Nolin TD, Leblond FA, Pichette V. Current understanding of drug disposition in kidney disease. J Clin Pharmacol. 2012;52:10S–22S.

    Article  CAS  PubMed  Google Scholar 

  71. Nolin TD, Unruh ML. Clinical relevance of impaired nonrenal drug clearance in ESRD. Semin Dial. 2010;23:482–5.

    Article  PubMed  Google Scholar 

  72. Dreisbach AW. The influence of chronic renal failure on drug metabolism and transport. Clin Pharmacol Ther. 2009;86:553–6.

    Article  CAS  PubMed  Google Scholar 

  73. Yeung CK, Shen DD, Thummel KE, Himmelfarb J. Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport. Kidney Int. 2014;85:522–8.

    Article  CAS  PubMed  Google Scholar 

  74. Velenosi TJ, Fu AYN, Luo S, Wang H, Urquhart BL. Down-regulation of hepatic CYP3A and CYP2C mediated metabolism in rats with moderate chronic kidney disease. Drug Metab Dispos. 2012;40:1508–14.

    Article  CAS  PubMed  Google Scholar 

  75. Joy MS, Frye RF, Nolin TD, Roberts BV, La MK, Wang J, et al. In vivo alterations in drug metabolism and transport pathways in patients with chronic kidney diseases. Pharmacotherapy. 2014;34:114–22.

    Article  CAS  PubMed  Google Scholar 

  76. Viell B, Krause B, Vestweber KH, Schaaf S, Scholl H. Transintestinal elimination of ciprofloxacin in humans–concomitant assessment of its metabolites in serum, ileum and colon. Infection. 1992;20:324–7.

    Article  CAS  PubMed  Google Scholar 

  77. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for Industry. Pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on dosing and labeling. 1998. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072127.pdf. Accessed 1 Sep 2013.

  78. Zhang Y, Zhang L, Abraham S, Apparaju S, Wu T-C, Strong JM, 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;85:305–11.

    Article  CAS  PubMed  Google Scholar 

  79. Ibrahim S, Honig P, Huang SM, Gillespie W, Lesko LJ, Williams RL. Clinical pharmacology studies in patients with renal impairment: past experience and regulatory perspectives. J Clin Pharmacol. 2000;40:31–8.

    Article  CAS  PubMed  Google Scholar 

  80. Huang S-M, Temple R, Xiao S, Zhang L, Lesko LJ. When to conduct a renal impairment study during drug development: US Food and Drug Administration perspective. Clin Pharmacol Ther. 2009;86:475–9.

    Article  CAS  PubMed  Google Scholar 

  81. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry. Pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on dosing and labeling. 2010. http://www.fda.gov/downloads/Drugs/.../Guidances/UCM204959.pdf. Accessed 1 Sep 2013.

  82. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.

    Article  CAS  PubMed  Google Scholar 

  83. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–70.

    Article  CAS  PubMed  Google Scholar 

  84. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.

    Article  PubMed Central  PubMed  Google Scholar 

  85. Wu C-Y, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22:11–23.

    Article  CAS  PubMed  Google Scholar 

  86. Shugarts S, Benet LZ. The role of transporters in the pharmacokinetics of orally administered drugs. Pharm Res. 2009;26:2039–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Reyes M, Benet LZ. Effects of uremic toxins on transport and metabolism of different biopharmaceutics drug disposition classification system xenobiotics. J Pharm Sci. 2011;100:3831–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Uchida N, Kurata N, Shimada K, Nishimura Y, Yasuda K, Hashimoto M, et al. Changes of hepatic microsomal oxidative drug metabolizing enzymes in chronic renal failure (CRF) rats by partial nephrectomy. Jpn J Pharmacol. 1995;68:431–9.

    Article  CAS  PubMed  Google Scholar 

  89. Dani M, Boisvert C, Michaud J, Naud J, Lefrançois S, Leblond FA, et al. Down-regulation of liver drug-metabolizing enzymes in a murine model of chronic renal failure. Drug Metab Dispos. 2010;38:357–60.

    Article  CAS  PubMed  Google Scholar 

  90. Kévorkian JP, Michel C, Hofmann U, Jacqz-Aigrain E, Kroemer HK, Peraldi MN, et al. Assessment of individual CYP2D6 activity in extensive metabolizers with renal failure: comparison of sparteine and dextromethorphan. Clin Pharmacol Ther. 1996;59:583–92.

    Article  PubMed  Google Scholar 

  91. Rostami-Hodjegan A, Kroemer HK, Tucker GT. In-vivo indices of enzyme activity: the effect of renal impairment on the assessment of CYP2D6 activity. Pharmacogenetics. 1999;9:277–86.

    Article  CAS  PubMed  Google Scholar 

  92. Dreisbach AW, Japa S, Gebrekal AB, Mowry SE, Lertora JJL, Kamath BL, et al. Cytochrome P4502C9 activity in end-stage renal disease. Clin Pharmacol Ther. 2003;73:475–7.

    Article  CAS  PubMed  Google Scholar 

  93. De Martin S, Orlando R, Bertoli M, Pegoraro P, Palatini P. Differential effect of chronic renal failure on the pharmacokinetics of lidocaine in patients receiving and not receiving hemodialysis. Clin Pharmacol Ther. 2006;80:597–606.

    Article  PubMed  Google Scholar 

  94. Frye RF, Matzke GR, Alexander ACM, Palevsky P, Rault R, Branch RA. Effect of renal insufficiency on CYP activity. Clin Pharmacol Ther. 1996;59:155.

    Article  Google Scholar 

  95. Vinik HR, Reves JG, Greenblatt DJ, Abernethy DR, Smith LR. The pharmacokinetics of midazolam in chronic renal failure patients. Anesthesiology. 1983;59:390–4.

    Article  CAS  PubMed  Google Scholar 

  96. Holzer B, Stieger B, Folkers G, Meier PJ, Fattinger K. Differential regulation of basolateral and canalicular transporter expression in rat liver in chronic renal failure. Clin Pharmacol Ther. 2005;77:P34.

    Article  Google Scholar 

  97. Veau C, Leroy C, Banide H, Auchère D, Tardivel S, Farinotti R, et al. Effect of chronic renal failure on the expression and function of rat intestinal P-glycoprotein in drug excretion. Nephrol Dial Transplant. 2001;16:1607–14.

    Article  CAS  PubMed  Google Scholar 

  98. Okabe H, Hasunuma M, Hashimoto Y. The hepatic and intestinal metabolic activities of P450 in rats with surgery- and drug-induced renal dysfunction. Pharm Res. 2003;20:1591–4.

    Article  CAS  PubMed  Google Scholar 

  99. Moon YJ, Lee AK, Chung HC, Kim EJ, Kim SH, Lee DC, et al. Effects of acute renal failure on the pharmacokinetics of chlorzoxazone in rats. Drug Metab Dispos. 2003;31:776–84.

    Article  CAS  PubMed  Google Scholar 

  100. Chung HC, Kim SH, Lee MG, Kim SG. Increase in urea in conjunction with L-arginine metabolism in the liver leads to induction of cytochrome P450 2E1 (CYP2E1): the role of urea in CYP2E1 induction by acute renal failure. Drug Metab Dispos. 2002;30:739–46.

    Article  CAS  PubMed  Google Scholar 

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No sources of funding were used to assist in the preparation of this review. The authors have no potential conflicts of interest that are directly relevant to the content of this review to declare.

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  1. Department of Pharmacy, Groupement Hospitalier Nord, Hospices Civils de Lyon, 103 Grande Rue de la Croix Rousse, 69317, Lyon Cedex 04, France

    Laure Lalande, Bruno Charpiat, Gilles Leboucher & Michel Tod

  2. Faculty of Pharmaceutical Sciences, University Claude Bernard Lyon 1, Lyon, France

    Michel Tod

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  1. Laure Lalande
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Lalande, L., Charpiat, B., Leboucher, G. et al. Consequences of Renal Failure on Non-Renal Clearance of Drugs. Clin Pharmacokinet 53, 521–532 (2014). https://doi.org/10.1007/s40262-014-0146-1

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