Effect of the potent CYP2D6 inhibitor sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy male Korean volunteers

Abstract

1. Recently, we demonstrated that sarpogrelate is a potent and selective CYP2D6 inhibitor in vitro. Here, we evaluated the effect of sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy subjects.

2. Nine healthy male subjects genotyped for CYP2D6*1/*1 or *1/*2 were included in an open-label, randomized, three treatment-period and crossover study. A single oral dose of metoprolol (100 mg) was administered with water (treatment A) and sarpogrelate (100 mg bid.; a total dose of 200 mg and treatment B), or after pretreatment of sarpogrelate for three days (100 mg tid.; treatment C). Plasma levels of metoprolol and α-hydroxymetoprolol were determined using a validated LC-MS/MS method. Changes in heart rate and blood pressure were monitored as pharmacodynamic responses to metoprolol.

3. Metoprolol was well tolerated in the three treatment groups. In treatment B and C groups, the AUC_t of metoprolol increased by 53% (GMR, 1.53; 90% CI, 1.17–2.31) and by 51% (1.51; 1.17–2.31), respectively. Similar patterns were observed for the increase in C_max of metoprolol by sarpogrelate. However, the pharmacodynamics of metoprolol did not differ significantly among the three treatment groups.

4. Greater systemic exposure to metoprolol after co-administration or pretreatment with sarpogrelate did not result in clinically relevant effects. Co-administration of both agents is well tolerated and can be employed without the need for dose adjustments.

• CYP2D6 inhibition
• drug–drug interaction
• metoprolol
• pharmacodynamics
• pharmacokinetics
• sarpogrelate

Declaration of interest

This research was supported by the Bio and Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science, ICT and Future Planning, Republic of Korea (No. 2013M3A9B5075838) and a grant from Global Centre of Excellence in Clinical Trials, Ministry for Health and Welfare, Republic of Korea (A070001). None of the authors declares any conflict of interest regarding this manuscript.