Effect of CYP2D6*10 on pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients

Abstract

Objective: This study was performed to evaluate the effect of mutant alleles CYP2D6*2 and CYP2D6*10 on the pharmacokinetics of routinely administered metoprolol in middle-aged and elderly Japanese patients.

Methods: We determined the genotypes of CYP2D6 in 34 patients aged from 56 years to 83 years, and analyzed the plasma concentration of metoprolol at steady state after repetitive administration. The pharmacokinetic parameters of metoprolol in individual patients were obtained from population estimates according to Bayes' theorem.

Results: The plasma concentrations of metoprolol in the patients with CYP2D6*1/*1 (group 1a) were similar to those in the patients with CYP2D6*1/*2 (group 1b). The plasma concentrations in the patients with CYP2D6*1/*10 (group 2a) were also similar to those in the patients with CYP2D6*2/*10 (group 2b) but were higher than those in group 1 (group 1a plus 1b). The plasma concentrations of metoprolol in the patients with CYP2D6*10/*10 (group 3) were significantly higher than those in group 1 and group 2 (group 2a plus 2b). Mean values of oral clearance (in l/h/kg) in Groups 1, 2, and 3 were estimated to be 1.2, 1.0, and 0.49, respectively. These oral clearance values of metoprolol estimated in middle-aged and elderly Japanese patients were lower than those estimated in healthy young Chinese reported previously.

Conclusion: The present study indicated that CYP2D6*10 is mainly responsible for the large pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients. In addition, the pharmacokinetics of repetitively administered metoprolol in middle-aged and elderly patients may be different from that of a single dose in younger patients. These results suggested that a lower dose of metoprolol may be used in middle-aged and elderly patients with CYP2D6*10.