The Effects of CKD on Cytochrome P450-Mediated Drug Metabolism

Abstract

CKD affects a significant proportion of the world's population, and the prevalence of CKD is increasing. Standard practice currently is to adjust the dose of renally eliminated medications as kidney function declines in effort to prevent adverse drug reactions. It is increasingly becoming recognized that CKD also impacts nonrenal clearance mechanisms such as hepatic and intestinal cytochrome P450 (CYP) enzymes and drug transport proteins, the latter of which is beyond the scope of this review. CYPs are responsible for the metabolism of many clinically used drugs. Genetics, patient factors (eg, age and disease) and drug interactions are well known to affect CYP metabolism resulting in variable pharmacokinetics and responses to medications. There now exists an abundance of evidence demonstrating that CKD can impact the activity of many CYP isoforms either through direct inhibition by circulating uremic toxins and/or by reducing CYP gene expression. Evidence suggests that reductions in CYP metabolism in ESRD are reversed by kidney transplantation and temporarily restored via hemodialysis. This review summarizes the current understanding of the effects that CKD can have on CYP metabolism and also discusses the impact that CYP metabolism phenotypes can have on the development of kidney injury.

Keywords: Cytochrome P-450 enzyme system; Drug metabolism; Pharmacogenetics; Pharmacokinetics; Renal insufficiency chronic.