Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Metoprolol in Routinely Treated Japanese Patients

• Taguchi Masato

  Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University

• Nozawa Takashi

  Second Department of Internal Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University

• Mizumaki Kouichi

  Second Department of Internal Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University

• Inoue Hiroshi

  Second Department of Internal Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University

• Tahara Katsutoshi

  Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University

• Takesono Chihiro

  Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University

• Hashimoto Yukiya

  Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University

Abstract

This study was performed to estimate the mean pharmacokinetic parameters of routinely administered metoprolol in middle-aged and elderly Japanese patients. Whole blood concentration data (65 samples) at steady-state following repetitive administration to 34 patients were analyzed using a nonlinear mixed effects model. A one-compartment model was parameterized in terms of oral clearance (CL/F) and apparent volume of distribution (V/F). We evaluated the effect of polymorphic alleles (CYP2D6*2, CYP2D6*10, CYP2C19*2 and CYP2C19*3), age, gender, and heart failure on the pharmacokinetic parameters of metoprolol. The CL/F value in patients homozygous for the CYP2D6*10 allele was 64% lower than that in patients with a CYP2D6*1/*1 or *1/*2 genotype. The CL/F value in older (>70 years old) patients was 26% lower than that in younger (≤70 years old) patients. In addition, the V/F value in patients homozygous for the CYP2D6*10 allele was 25% lower than that in patients with the CYP2D6*1/*1 or *1/*2 genotype. On the other hand, the CYP2C19 genotype, gender, and heart failure showed no significant effects on the pharmacokinetics of metoprolol. The results suggest that the pharmacokinetic variability of metoprolol in Japanese extensive metabolizers of CYP2D6 is very large, probably because CYP2D6*10 is responsible not only for the decreased systemic clearance (CL) but also for the increased bioavailability (F) of the drug.

Journal

• Biological and Pharmaceutical Bulletin

  Biological and Pharmaceutical Bulletin 27 (10), 1642-1648, 2004

  The Pharmaceutical Society of Japan

Keywords

• aging
• Japanese patient
• metoprolol
• nonlinear mixed effects model (NONMEM)
• pharmacokinetics
• whole blood concentration

Details

• CRID: 1390282679601473408
• NII Article ID: 110003608670
• NII Book ID: AA10885497
• DOI: 10.1248/bpb.27.1642
• COI: 1:CAS:528:DC%2BD2cXhtFSitL%2FP
• ISSN: 13475215
• ISSN: 09186158
• NDL BIB ID: 7097743
• PubMed: 15467211
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I7097743
• Web Site: http://www.jstage.jst.go.jp/article/bpb/27/10/27_10_1642/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2006205046
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed