Down-regulation of hepatic CYP3A and CYP2C mediated metabolism in rats with moderate chronic kidney disease

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Thomas J VelenosiBradley L Urquhart

Abstract

Expression and activity of drug-metabolizing enzymes are decreased in severe kidney disease; however, only a small percentage of patients with chronic kidney disease (CKD) are at the final stage of the disease. This study aimed to determine the changes in drug-metabolizing enzyme function and expression in rats with varying degrees of kidney disease. Sprague-Dawley rats were subjected to surgical procedures that allowed the generation of three distinct models of kidney function: normal kidney function, moderate kidney function, and severe kidney disease. Forty-two days after surgery, rats were sacrificed and hepatic CYP3A and CYP2C expression was determined. In addition, enzymatic activity was determined in liver microsomes by evaluating midazolam (CYP3A), testosterone (CYP3A and CYP2C), and tolbutamide (CYP2C) enzyme kinetics. Both moderate and severe kidney disease were associated with a reduction in CYP3A2 and CYP2C11 expression (p < 0.05). Likewise, moderate kidney disease resulted in more than a 60% decrease in enzyme activity (V(max)) for CYP2C11 and CYP3A, compared with controls (p < 0.05). When the degree of kidney disease was correlated with metabolic activity, an exponential decline in CYP2C- and CYP3A-mediated metabo...Continue Reading

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Citations

May 28, 2014·Clinical Pharmacokinetics·Laure LalandeMichel Tod
Jun 26, 2014·Expert Opinion on Drug Metabolism & Toxicology·Thomas J Velenosi, Bradley L Urquhart
Oct 1, 2013·Expert Opinion on Drug Metabolism & Toxicology·Barbara J PhilipsIain Macphee
Apr 12, 2015·Néphrologie & thérapeutique·Judith NaudVincent Pichette
Dec 3, 2014·American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation·Benjamin K A ThomsonBradley L Urquhart
Jul 1, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yuki HoriTetsuya Aiba
Jul 7, 2018·Biopharmaceutics & Drug Disposition·Shuhei FukunoHiroki Konishi
Mar 10, 2018·Clinical Journal of the American Society of Nephrology : CJASN·Alvin TieuBradley L Urquhart
Feb 16, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yuan WeiHongyu Wang
Jul 18, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sara De MartinPietro Palatini
Nov 12, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Gurjeev SohiDaniel B Hardy
Oct 22, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Osama Y AlshogranThomas D Nolin
Sep 12, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Thomas J VelenosiBradley L Urquhart
Jun 15, 2020·Cardiovascular Drugs and Therapy·Pietro ScicchitanoMarco Matteo Ciccone
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Jul 9, 2020·Pharmacological Reports : PR·Máté Tamás DériKatalin Monostory
May 3, 2019·Pharmacology Research & Perspectives·Andrew S KuceyBrad L Urquhart

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