title: Inhibitory and stimulative effects of amiodarone on metabolism of carvedilol in human liver microsomes.
abstract: It was reported that coadministration of amiodarone with carvedilol increased the serum concentration to dose (C/D) ratio of S-carvedilol in patients with heart failure, but not of R-carvedilol. The aim of the present study was to investigate the effect of amiodarone and its metabolite on the metabolism of R- and S-carvedilol in human liver microsomes (HLM). Oxidation of carvedilol in HLM was evaluated in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH), whereas glucuronidation was evaluated in the presence of uridine 5'-diphosphate (UDP)-glucuronic acid. The oxidation and glucuronidation activities of HLM for S-carvedilol were approximately 2- and 4-fold greater, respectively, than those for R-carvedilol. In the presence of amiodarone (50 microM) and/or desethylamiodarone (25 microM), the oxidation activity for R- and S-carvedilol decreased significantly. In contrast, the glucuronidation activity for R-carvedilol was increased 1.6- and 1.4-fold by amiodarone and desethylamiodarone, respectively, whereas the glucuronidation of S-carvedilol was only slightly changed by amiodarone and desethylamiodarone. These results suggested that inhibition of S-carvedilol oxidation by amiodarone and/or desethylamiodarone is implicated in the increased C/D ratio of S-carvedilol associated with coadministration of amiodarone. On the other hand, the stimulative effect of amiodarone and/or desethylamiodarone on the glucuronidation of R-carvedilol may compensate for the inhibitory effect of those on R-carvedilol oxidation.
authors.affiliation: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Horiuchi
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kato
authors.forename: Arisa
authors.initials: A
authors.lastname: Nakamura
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ishida
authors.forename: Masato
authors.initials: M
authors.lastname: Taguchi
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D000638:Amiodarone / Q000008:administration & dosage / Q000494:pharmacology*; D002227:Carbazoles / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D000077261:Carvedilol; D004347:Drug Interactions; D006801:Humans; D007536:Isomerism; D050217:Metabolic Detoxication, Phase II; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D009249:NADP; D010084:Oxidation-Reduction; D011412:Propanolamines / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D014535:Uridine Diphosphate Glucuronic Acid
chemical_list: D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D014535:Uridine Diphosphate Glucuronic Acid; D009249:NADP; D000638:Amiodarone