Effect of the potent CYP2D6 inhibitor sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy male Korean volunteers. (March 2015)

• Record Type: Journal Article
• Authors: Cho, Doo-Yeoun; Bae, Soo Hyeon; Lee, Joeng Kee; Park, Jung Bae; Kim, Yang-Weon; Lee, Sukhyang; Oh, Euichaul; Kim, Bom-Taeck; Bae, Soo Kyung
• Is Part Of: Xenobiotica. Volume 45:Number 3(2015:Mar.)
• Page Start: 256
• Page End: 263
• Publication Date: 2015-03
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2014.967824
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. Recently, we demonstrated that sarpogrelate is a potent and selective CYP2D6 inhibitor <italic>in vitro</italic>. Here, we evaluated the effect of sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy subjects.</p> <p>2. Nine healthy male subjects genotyped for <italic>CYP2D6</italic>*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.</p> <p>3. Metoprolol was well tolerated in the three treatment groups. In treatment B and C groups, the AUC<italic><sub>t</sub></italic> 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 <italic>C</italic><sub>max</sub> of metoprolol by sarpogrelate. However, the pharmacodynamics of metoprolol did not differ significantly among the three treatment groups.</p> <p>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.</p> </abstract>