Multiple Regression Analysis of Pharmacogenetic Variability of Carvedilol Disposition in 54 Healthy Japanese Volunteers

• Honda Mutsuko

  Graduate School of Pharmaceutical Sciences, University of Toyama

• Ogura Yumi

  Graduate School of Pharmaceutical Sciences, University of Toyama

• Toyoda Wakako

  Graduate School of Pharmaceutical Sciences, University of Toyama

• Taguchi Masato

  Graduate School of Pharmaceutical Sciences, University of Toyama

• Nozawa Takashi

  Second Department of Internal Medicine, Faculty of Medicine, University of Toyama

• Inoue Hiroshi

  Second Department of Internal Medicine, Faculty of Medicine, University of Toyama

• Hashimoto Yukiya

  Graduate School of Pharmaceutical Sciences, University of Toyama

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.

Journal

• Biological and Pharmaceutical Bulletin

  Biological and Pharmaceutical Bulletin 29 (4), 772-778, 2006

  The Pharmaceutical Society of Japan

Keywords

• carvedilol
• <i>CYP2D6*10</i>
• pharmacokinetics
• Bayesian analysis

Details

• CRID: 1390001204627961088
• NII Article ID: 110005602184
• NII Book ID: AA10885497
• DOI: 10.1248/bpb.29.772
• COI: 1:CAS:528:DC%2BD28XkslOit7Y%3D
• ISSN: 13475215
• ISSN: 09186158
• NDL BIB ID: 7861863
• PubMed: 16595916
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I7861863
• Web Site: https://www.jstage.jst.go.jp/article/bpb/29/4/29_4_772/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2007050221
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed