title: 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 AUCt 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 Cmax 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.
authors.affiliation: Department of Family Practice and Community Health, Ajou University School of Medicine , Yeongtong-gu, Suwon , South Korea .
authors.forename: Doo-Yeoun
authors.initials: DY
authors.lastname: Cho
authors.forename: Soo Hyeon
authors.initials: SH
authors.lastname: Bae
authors.forename: Joeng Kee
authors.initials: JK
authors.lastname: Lee
authors.forename: Jung Bae
authors.initials: JB
authors.lastname: Park
authors.forename: Yang-Weon
authors.initials: YW
authors.lastname: Kim
authors.forename: Sukhyang
authors.initials: S
authors.lastname: Lee
authors.forename: Euichaul
authors.initials: E
authors.lastname: Oh
authors.forename: Bom-Taeck
authors.initials: BT
authors.lastname: Kim
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Bae
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008875:Middle Aged; D056910:Republic of Korea; D013386:Succinates / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D013386:Succinates; C064294:sarpogrelate; C029504:alpha-hydroxymetoprolol; D008790:Metoprolol
keywords: CYP2D6 inhibition; drug–drug interaction; metoprolol; pharmacodynamics; pharmacokinetics; sarpogrelate