Effect of CYP2D6*10 on the Pharmacokinetics of R- and S-Carvedilol in Healthy Japanese Volunteers

Abstract

Carvedilol is a b-adrenoceptor antagonist, and has been clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias. [1][2][3][4] Carvedilol is highly lipophilic and eliminated predominantly by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose.5) The drug is absorbed rapidly from the gastrointestinal tract after oral administration; however, the amount of unchanged drug excreted in the feces was 23% of the administered dose probably because of incomplete intestinal absorption.6) In addition, orally administered carvedilol undergoes stereoselective first-pass metabolism, and the maximal plasma concentration of R-enantiomer with low b-blocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.6) The mean absolute bioavailability of R-and S-enantiomer in humans is 31% and 15%, respectively. 7)It was reported that CYP2D6 in microsomes derived from lymphoblastoid cells with human cDNA shows strong enzyme activity for the metabolism of R-and S-carvedilol. 8)Poor metabolism through CYP2D6 was found in 7% of Caucasian subjects, and two common defective alleles responsible for the poor metabolism are CYP2D6*4 and *5.9) The gene frequency of individual variants of CYP2D6 shows a marked interethnic difference, and poor metabolism is found in less than 1% of Asian subjects. 9) Among Asian extensive/ intermediate metabolizers, the three most common alleles of the CYP2D6 gene are CYP2D6*1, *2, and *10. The mutant allele of CYP2D6 (CYP2D6*2) does not affect the enzyme activity, whereas the CYP2D6*10 allele causes the low expression and affinity of CYP2D6. 10,11) In the present study, we estimated the pharmacokinetic parameters of R-and S-carvedilol in 23 healthy Japanese volunteers by the Bayesian method using a nonlinear mixed effects model (NONMEM) program. We then examined the effect of the CYP2D6 polymorphisms on the stereoselective pharmacokinetics of carvedilol. MATERIALS AND METHODS Subjects and Study ProtocolsTwenty-three healthy Japanese volunteers (19 men and 4 women) participated in this study. The age was between 22 and 44 years old (mean: 29.1), and the body weight was between 47 and 86 kg (mean: 64.7). They were given 5 mg (two 2.5 mg-tablets: 7 men and 2 women) or 10 mg (one 10 mg-tablet: 12 men and 2 women) of carvedilol (Artist ® tablet; Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan) at least 2 h before a meal, because the peak blood drug concentrations are attained at 0.5-1 h after oral administration following an over night fast.12) Carvedilol was taken with a glass of water, and 5 ml of blood was taken at 2 and 6 h after dosing. All the subjects were physicians or pharmacists, and they chose the dose of carvedilol by themselves. The mean (ϮS.D.) body weight in the subjects taking 5 mg and 10 mg carvedilol was 57.9Ϯ6.7 kg and 69.1Ϯ 9.9 kg, respectively. They all gave written consent to participate in this study, which was approved by the ethics committee of Toyama Medica...

Inhibitory and Stimulative Effects of Amiodarone on Metabolism of Carvedilol in Human Liver Microsomes

“…[13][14][15] Assay of Carvedilol Enantiomers The amount of carvedilol in the samples was measured using chiral high performance liquid chromatography (HPLC) as described by Saito et al with minor modifications. [7][8][9][10]16) Briefly, carvedilol was extracted from the samples (0.1 ml) with 5 ml diethylether after alkalization in 3 ml of 0.1 M Britton-Robinson buffer (pH 8.5). The organic phase was transferred and evaporated dry in a water bath at 45°C.…”

“…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][8][9][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.…”

Involvement of the CYP1A Subfamily in Stereoselective Metabolism of Carvedilol in .BETA.-Naphthoflavone-Treated Caco-2 Cells

“…The cells were seeded at a density 5ϫ10 5 The treatment of Caco-2 cells with b-NF or VD 3 (an inducer of CYP3A4) was performed as described previously. Reverse transcription of extracted total RNA was performed using an Omniscript ® RT Kit (QIAGEN) and random hexamer (QIAGEN) according to the manufacturer's instructions.…”

“…[3][4][5] Carvedilol is metabolized extensively via aliphatic side-chain oxidation, aromatic ring oxidation, and conjugation pathways.6) Oldham and Clarke reported that oxidative activity of carvedilol is observed in cytochrome P450 (CYP) 2D6, 1A2, 3A4, and 2C9.7) In addition, Ohno et al reported that UDPglucuronosyltransferase (UGT) 2B7, 1A1, and 2B4 are capable of catalyzing the glucuronidation of carvedilol.8) However, it has been unknown whether the intestine also plays a role in the first-pass presystemic metabolism of carvedilol, although several CYP and UGT isoforms are expressed in human intestinal epithelial cells. 9,10) We previously investigated the metabolism of carvedilol in human intestinal epithelial Caco-2 cells.…”

“…[3][4][5] Carvedilol is metabolized extensively via aliphatic side-chain oxidation, aromatic ring oxidation, and conjugation pathways.…”