title: Effect of CYP2D6*10 on the pharmacokinetics of R- and S-carvedilol in healthy Japanese volunteers.
abstract: This study was performed to investigate the effect of CYP2D6*10 on the pharmacokinetics of R- and S-carvedilol in healthy Japanese volunteers. Five or 10 mg of carvedilol was orally administered to 23 subjects (22-44 years old), and blood samples were taken at 2 and 6 h after dosing. We determined the polymorphic alleles of CYP2D6 in each subject. The whole blood concentration of R- and S-carvedilol was measured by an HPLC method. The pharmacokinetic parameters in individual subjects were estimated by the Bayesian method using the nonlinear mixed effects model (NONMEM) program. The mean values of oral clearance for R- and S-carvedilol were estimated to be 1.01 and 2.15 l/h/kg, respectively. The oral clearance was highly correlated with the apparent volume of distribution among the subjects, suggesting that the interindividual difference in bioavailability was largely responsible for the pharmacokinetic variability of carvedilol. The oral clearance and also volume of distribution of both enantiomers were significantly lower in the subjects with the CYP2D6*10 allele than with the CYP2D6*1/*1 or *1/*2 genotype. These results suggested that the systemic and/or pre-systemic metabolism of R- and S-carvedilol in the liver is significantly decreased in Japanese with the CYP2D6*10 allele.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Honda
authors.forename: Takashi
authors.initials: T
authors.lastname: Nozawa
authors.forename: Norio
authors.initials: N
authors.lastname: Igarashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Rie
authors.initials: R
authors.lastname: Arakawa
authors.forename: Yumi
authors.initials: Y
authors.lastname: Ogura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Okabe
authors.forename: Masato
authors.initials: M
authors.lastname: Taguchi
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D000328:Adult; D002227:Carbazoles / Q000097:blood / Q000493:pharmacokinetics*; D000077261:Carvedilol; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D011412:Propanolamines / Q000097:blood / Q000493:pharmacokinetics*; D012016:Reference Values; D013237:Stereoisomerism
chemical_list: D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D019389:Cytochrome P-450 CYP2D6