Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes

Objective: CYP2D6 mediates both a-hydroxylation and O-demethylation of meto prolol, In Chinese subjects, CYP2D6*1 (the wild-type) alleles are relativel y uncommon. Subjects with P34S (C-188-->T-188) and S486T (G(4268)-->C-4268) mutations (CYP2D6J or CYP2D6*10A) are more frequently seen. Recently, the CYP2D6*2 (CYP2D6L) genotype that results in R296C (C-2938-->T-2938) and S48 6T mutations was also found important, In this study, metoprolol pharmacoki netics was investigated in subjects of these 3 major genotypes, Methods: Allele-specific polymerase chain reaction was used to differentiat e CYP2D6*1 and CYP2D6*2 alleles from the common CYP2D6*10A allele in Chines e. Subjects with both CYP2D6*1 and CYP2D6*2 have homozygous C-188 in the ex on 1, whereas subjects with CYP2D6*10A have T-188. Metoprolol pharmacokinet ics was compared in 16 C-188 subjects (6 homozygous CYP2D6*1 subjects and 1 0 heterozygous CYP2D6*1/CYP2D6*2 subjects), 12 heterozygous C/T-188 subject s, and 12 homozygous T-188 subjects. Results: No significant difference in plasma concentration profile or urina ry alpha-hydroxymetoprolol excretion could be found among subjects with R29 6C polymorphism (CYP2D6*1/CYP2D6*2). Therefore data from subjects with CYP2 D6*1 and CYP2D6*2 were pooled to compare with data from subjects with CYP2D 6*10A. The area under plasma concentration curves (AUC) of S-metoprolol was 1411 +/- 116 (mean +/- SEM, n = 16), 1899 +/- 120 (n = 12), and 3588 +/- 4 35 (n = 12) nmol.hr/L for homozygous C-188, heterozygous C/T-188, and homoz ygous T-188 subjects, respectively. The urinary recovery of all 4 alpha-hyd roxymetoprolol diastereomers was significantly lower in T-188 subjects than in C-188 subjects. Conclusion: The P34S polymorphism but not the R296C polymorphism resulted i n higher metoprolol plasma concentrations and lower urinary metoprolol meta bolite levels in Chinese subjects. This finding suggests that a lower dose of metoprolol may be used in subjects with T-188 mutation ( CYP2D6*10A alle le).