Multiple regression analysis of pharmacogenetic variability of carvedilol disposition in 54 healthy Japanese volunteers

Mutsuko Honda, Yumi Ogura, Wakako Toyoda, Masato Taguchi, Takashi Nozawa, Hiroshi Inoue, Yukiya Hashimoto*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

The aim of this study was to evaluate the pharmacogenetic variability in the disposition of carvedilol in the Japanese population. Five or 10 mg of carvedilol was orally administered to 54 healthy Japanese subjects (22-44 years old), and blood samples were taken at 2 and 6 h after dosing. We determined the polymorphic alleles of CYP2D6, CYP2C9, CYP2C19, CYP3A5, UGT2B7, and MDR1 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. We then examined the effect of the genetic polymorphisms on the variability in the pharmacokinetics of carvedilol using a multiple regression analysis. The oral clearance (CL/F) and also apparent volume of distribution (V/F) of both enantiomers were significantly lower in the subjects with the CYP2D6*10 allele than those with the CYP2D6*1/*1, *1/*2, or *2/*2 genotype, confirming our previous finding that the bioavailability (F) and systemic clearance (CL) of R- and S-carvedilol in the liver is significantly altered in Japanese with the CYP2D6*10 allele. On the other hand, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, and MDR1 C3435T did not significantly affect the pharmacokinetics of carvedilol in Japanese subjects.

Original languageEnglish
Pages (from-to)772-778
Number of pages7
JournalBiological and Pharmaceutical Bulletin
Volume29
Issue number4
DOIs
StatePublished - 2006/04

Keywords

  • Bayesian analysis
  • CYP2D6*10
  • Carvedilol
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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