Pharmacokinetics and pharmacodynamics characterization of subjects with novel CYP2D6 genotypes using probe drug metoprolol

Abstract

Purpose To investigate the pharmacokinetic profile and pharmacodynamics characterization of volunteers who carries newly discovered CYP2D6 genotypes. Methods Totally, 22 volunteers were recruited in the study. The peripheral blood and urine were collected at the indicated time after orally administration of metoprolol. After sample preparation, a validated HPLC method was employed to determine metoprolol and α-hydroxymetoprolol. Meanwhile, the blood pressure and electrocardiogram of the subjects were monitored. Results The results demonstrated that the main pharmacokinetic parameters of analytes in CYP2D6*1/*34 were comparable to CYP2D6*1/*1. The AUC and t1/2 in CYP2D6*10/*87, CYP2D6*10/*95 and CYP2D6*97/*97 carriers increased by 2–3 times comparing to wild-type. The urine metabolic rate of metoprolol in these genotypes carriers were in consistence to the tendencies obtained from plasma samples. Therefore, CYP2D6*1/*34 can be assigned as normal metabolizer, while CYP2D6*10/*87, CYP2D6*10/*95 and CYP2D6*97/*97 were intermediate metabolizers. Although the blood concentration of metoprolol is correlated with genotype of CYP2D6, its blood pressure lowering effect is saturated at the maximum efficacy at 25 mmHg. In addition, the P-Q interval prolongation and heart rate lowing were not positively correlated with metoprolol blood exposure. Conclusion Based on the pharmacokinetics-pharmacodynamics model, this study clarified the characteristics of metoprolol with novel CYP2D6 genotypes, and provided a solid basic data for translational medicine of substrate drug.