title: Possibility of decrease in CYP1A2 function in patients with end-stage renal disease.
abstract: Propranolol, the substrate of cytochrome P450 (CYP) 1A2 and CYP2D6, has been reported to be in high concentrations in end-stage renal disease (ESRD) patients. This has been thought to be due to the decrease in the nonrenal clearance of propranolol. The objective of this study is to elucidate the reason for the decrease in nonrenal clearance in ESRD patients. CYP1A2 and CYP2D6 activities were estimated by the phenacetin O-deethylation and methoprolol O-demethylation methods, respectively. Pooled normal serum and pooled uremic serum were deproteinized by methanol in order to exclude high-molecular-weight compounds. We selected as candidate inhibitors: uremic toxins such as 3-indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, indole-3-acetic acid, and hippuric acid, and xanthine derivatives such as allantoin, uric acid, and xanthine. In this study, uremic serum was found to inhibit the CYP1A2-mediated metabolism of phenacetin to acetaminophen in a concentration-dependent and competitive manner. Xanthine also inhibited the metabolism of CYP1A2. On the other hand, uremic serum and the four uremic toxins did not inhibit the CYP2D6-mediated metabolism of metoprolol to O-demethylmetoprolol. In conclusion, this study suggests that the increase of the bioavailability of propranolol in ESRD is partly induced by the inhibition of the hepatic metabolism of CYP1A2 by xanthine in the uremic serum.
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsujimoto
authors.forename: Sari
authors.initials: S
authors.lastname: Sugimoto
authors.forename: Makiko
authors.initials: M
authors.lastname: Nagatomo
authors.forename: Taku
authors.initials: T
authors.lastname: Furukubo
authors.forename: Satoshi
authors.initials: S
authors.lastname: Izumi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamakawa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Minegaki
authors.forename: Kohshi
authors.initials: K
authors.lastname: Nishiguchi
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D006801:Humans; D007676:Kidney Failure, Chronic / Q000201:enzymology*; D008099:Liver / Q000378:metabolism; D008790:Metoprolol / Q000493:pharmacokinetics; D014511:Uremia / Q000378:metabolism
chemical_list: D000082:Acetaminophen; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol
keywords: Cytochrome P450; Drug metabolism; Uremic serum; Uremic toxins; Xanthine derivatives