title: Down-regulation of hepatic CYP3A and CYP2C mediated metabolism in rats with moderate chronic kidney disease.
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 metabolism was observed. Our results demonstrate that CYP3A and CYP2C expression and activity are decreased in both moderate and severe CKD. Our data suggest that drug metabolism is significantly decreased in the earlier stages of CKD and imply that patients with moderate CKD may be subject to unpredictable pharmacokinetics.
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Velenosi
authors.forename: Angel Y N
authors.initials: AY
authors.lastname: Fu
authors.forename: Shuhua
authors.initials: S
authors.lastname: Luo
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Urquhart
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001835:Body Weight; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D015536:Down-Regulation; D007527:Isoenzymes / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000201:enzymology / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D007527:Isoenzymes; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System