Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes.
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.


CONCLUSIONS
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).
Huang
J
J
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. jinding@mail.ncku.edu.tw
Chuang
S K
SK
Cheng
C L
CL
Lai
M L
ML
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008745:Methylation; D008790:Metoprolol / Q000493:pharmacokinetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012016:Reference Values; D013624:Taiwan
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol