Carvedilol is a b-adrenoceptor antagonist that has been clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmia. 1) Orally administered carvedilol undergoes stereoselective first-pass metabolism, and the blood concentration of S-enantiomer with high b-blocking activity is approximately one-half of that of R-enantiomer with low b-blocking activity. 2,3) Both enantiomers are mostly eliminated by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose. 4) Carvedilol is metabolized extensively via aliphatic side-chain oxidation, aromatic ring oxidation, and conjugation pathways. 5) Oldham and Clarke reported that the oxidative metabolism of carvedilol is mediated by cytochrome P450 (CYP) 2D6, 2C9, 3A4, and 1A2 in microsomes from human lymphoblastoid cells expressing human CYP. 6) In addition, our previous findings indicated that R-carvedilol is metabolized mainly by CYP2D6 and partly by CYP1A2, 2C9, and 3A4, and that S-carvedilol is metabolized mainly by CYP1A2 and partly by CYP2C9, 2D6, and 3A4. 7-10) On the other hand, Ohno et al. found that uridine 5Ј-diphosphate (UDP)-glucuronosyltransferase (UGT) 2B7, 2B4, and 1A1 are capable of catalyzing the glucuronidation of carvedilol using microsomes from insect cells expressing human UGT. 11) In addition, they have demonstrated that glucuronidation of R-carvedilol is mediated by UGT1A1 and 2B4, and that glucuronidation of S-carvedilol is mediated by UGT2B7 and 2B4. 11) In 2005, Fukumoto et al. reported the effect of amiodarone on the stereoselective pharmacokinetics of carvedilol in patients with heart failure. 12) That is, they demonstrated that the mean serum concentration to dose (C/D) ratio of S-carvedilol in 54 patients who took amiodarone concomitantly with carvedilol was 2-fold higher than that in 52 patients who took carvedilol alone. On the other hand, there was no significant difference in the mean C/D values of R-carvedilol between the two groups. 12) They speculated that the oxidative metabolism of only S-carvedilol might be markedly inhibited by coadministration of amiodarone; however, the effects of amiodarone and/or its metabolite on the oxidation and glucuronidation of carvedilol enantiomers are still unresolved. 12) In the present study, to evaluate the mechanism responsible for the interaction between carvedilol and amiodarone, we investigated inhibitory and stimulative effects of amiodarone and desethylamiodarone on the metabolism of R-and S-carvedilol in human liver microsomes (HLM). The 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 UDP-glucuronic acid (UDPGA).
MATERIALS AND METHODS
MaterialsCarvedilol was kindly supplied by Daiichi Sankyo Co., Ltd. (Tokyo, Japan). NADPH was obtained from Kohjin Co., Ltd. (Tokyo, Japan). UDPGA trisodium salt, amiodarone hydrochloride, furafylline, sulfaphenazole, and quinidine hydrochloride...