Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes

Clin Pharmacol Ther. 1999 Apr;65(4):402-7. doi: 10.1016/S0009-9236(99)70134-7.


Objective: CYP2D6 mediates both alpha-hydroxylation and O-demethylation of metoprolol. In Chinese subjects, CYP2D6*1 (the wild-type) alleles are relatively uncommon. Subjects with P34S (C188-->T188) and S486T (G4268-->C4268) mutations (CYP2D6J or CYP2D6*10A) are more frequently seen. Recently, the CYP2D6*2 (CYP2D6L) genotype that results in R296C (C2938-->T2938) and S486T mutations was also found important. In this study, metoprolol pharmacokinetics was investigated in subjects of these 3 major genotypes.

Methods: Allele-specific polymerase chain reaction was used to differentiate CYP2D6*1 and CYP2D6*2 alleles from the common CYP2D6*10A allele in Chinese. Subjects with both CYP2D6*1 and CYP2D6*2 have homozygous C188 in the exon 1, whereas subjects with CYP2D6*10A have T188. Metoprolol pharmacokinetics was compared in 16 C188 subjects (6 homozygous CYP2D6*1 subjects and 10 heterozygous CYP2D6*1/CYP2D6*2 subjects), 12 heterozygous C/T188 subjects, and 12 homozygous T188 subjects.

Results: No significant difference in plasma concentration profile or urinary alpha-hydroxymetoprolol excretion could be found among subjects with R296C polymorphism (CYP2D6*1/CYP2D6*2). Therefore data from subjects with CYP2D6*1 and CYP2D6*2 were pooled to compare with data from subjects with CTP2D6*10A. The area under plasma concentration curves (AUC) of S-metoprolol was 1411+/-116 (mean +/- SEM, n = 16), 1899+/-120 (n = 12), and 3588+/-435 (n = 12) nmol x hr/L for homozygous C188, heterozygous C/T188, and homozygous T188 subjects, respectively. The urinary recovery of all 4 alpha-hydroxymetoprolol diastereomers was significantly lower in T188 subjects than in C188 subjects.

Conclusion: The P34S polymorphism but not the R296C polymorphism resulted in higher metoprolol plasma concentrations and lower urinary metoprolol metabolite levels in Chinese subjects. This finding suggests that a lower dose of metoprolol may be used in subjects with T188 mutation (CYP2D6*10A allele).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adrenergic beta-Antagonists / blood
  • Adrenergic beta-Antagonists / pharmacokinetics*
  • Adrenergic beta-Antagonists / urine
  • Adult
  • Anti-Arrhythmia Agents / blood
  • Anti-Arrhythmia Agents / pharmacokinetics*
  • Anti-Arrhythmia Agents / urine
  • Antihypertensive Agents / blood
  • Antihypertensive Agents / pharmacokinetics*
  • Antihypertensive Agents / urine
  • Area Under Curve
  • Asian People / genetics*
  • Cytochrome P-450 CYP2D6 / genetics*
  • Genotype
  • Humans
  • Hydroxylation
  • Male
  • Methylation
  • Metoprolol / pharmacokinetics*
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Reference Values
  • Taiwan


  • Adrenergic beta-Antagonists
  • Anti-Arrhythmia Agents
  • Antihypertensive Agents
  • Cytochrome P-450 CYP2D6
  • Metoprolol