Influence ofCYP2D6*10on the pharmacokinetics of metoprolol in healthy Korean volunteers

Abstract

Genetic polymorphism of CYP2D6 leads to differences in pharmacokinetics of CYP2D6 substrates. The CYP2D6*10 allele is clinically important in Koreans because of its high frequency in Asians. We investigated whether the pharmacokinetics of metoprolol was altered by the presence of the CYP2D6*10 allele in Korean subjects. One hundred and seven volunteers were recruited and grouped as CYP2D6*1/*1, CYP2D6*1/*10 and CYP2D6*10/*10 according to their genotypes. Metoprolol tartrate 100 mg (Betaloc) was administered orally once to each subject in these three groups (n = 6, 7 and 5, respectively). The pharmacokinetic parameters of metoprolol and its metabolite, alpha-hydroxymetoprolol, and the metabolic ratio for the three groups were estimated and compared. The area under the plasma concentration-time curve (AUC(0-->infinity)), the maximum plasma concentration (C(max)) and the elimination half-life (T(1/2)) of metoprolol and alpha-hydroxymetoprolol for the CYP2D6*10/*10 group were all significantly different from those of the CYP2D6*1/*1 group (P < 0.05). The AUC(0-->infinity)s of metoprolol were 443.7 +/- 168.1, 995.6 +/- 321.4 and 2545.3 +/- 632.0 ng.h/mL, and the AUC(0-->infinity)s of alpha-hydroxymetoprolol were 1232.0 +/- 311.2, 1344.0 +/- 288.1 and 877.4 +/- 103.4 ng.h/mL for groups CYP2D6*1/*1, *1/*10 and *10/*10, respectively. The corresponding T(1/2) values of metoprolol were 2.7 +/- 0.5, 3.2 +/- 1.3 and 5.0 +/- 1.1 h, while those of alpha-hydroxymetoprolol were 5.4+/-1.5, 6.0 +/- 1.4 and 10.5 +/- 4.2 h, respectively. The metabolic ratios of the three groups were significantly different (P < 0.05). The CYP2D6*10 allele altered the pharmacokinetics of metoprolol in Korean subjects and is likely to affect other drugs metabolized by the CYP2D6 enzyme, similarly.