CYP2D6 Inhibitory Activities of Sarpogrelate hydrochloride and Drug-Drug Interaction
type: CreativeWork
description: Sarpogrelate has inhibitory effects on serotonin-induced platelet aggregation, thrombus formation, vasoconstriction and vascular smooth muscle cell proliferation, all of which are mediated by 5-HT2A receptors, and consequently reduces the ischemic symptoms associated with peripheral artery disease. Despite the wide use and excellent pharmacological actions of sarpogrelate, to date there is no information regarding the potential inhibitory effects of sarpogrelate and M-1 (an active metabolite of sarpogrelate) on CYP isoforms or drug–drug interactions. Using a cocktail assay, the effects of sarpogrelate and M-1 on nine CYP isoforms were measured by specific marker reactions in human liver microsomes. Nine healthy male subjects genotyped for CYP2D6*1/*1 or *1/*2 were included in a randomized, open-label, three-treatment three-period, 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; treatment B), or after pretreatment of sarpogrelate for 3 days (100 mg tid.; treatment C). Plasma levels of metoprolol and α-hydroxymetoprolol were determined using a validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) method. Changes in heart rate and blood pressure were monitored as pharmacodynamic responses to metoprolol. Sarpogrelate potently and selectively inhibited CYP2D6-mediated dextromethorphan O-demethylation with an IC50 (Ki) value of 3.05 μM (1.24 μM), in a competitive manner. M-1 also markedly inhibited CYP2D6 activity; its inhibitory effect with an IC50 (Ki) value of 0.201 μM (0.120 μM) was more potent than that of sarpogrelate. Co-administration of sarpogrelate increased the area under the plasma concentration–time curve from time zero to the last measurement (AUCt) of metoprolol increased by 53% (geometric mean ratio [GMR], 1.53; 90% confidence interval [CI], 1.09–2.32) and by 51% (1.51; 1.04–2.30), respectively. Similar patterns were observed for the in…
abstract: Sarpogrelate has inhibitory effects on serotonin-induced platelet aggregation, thrombus formation, vasoconstriction and vascular smooth muscle cell proliferation, all of which are mediated by 5-HT2A receptors, and consequently reduces the ischemic symptoms associated with peripheral artery disease. Despite the wide use and excellent pharmacological actions of sarpogrelate, to date there is no information regarding the potential inhibitory effects of sarpogrelate and M-1 (an active metabolite of sarpogrelate) on CYP isoforms or drug–drug interactions. Using a cocktail assay, the effects of sarpogrelate and M-1 on nine CYP isoforms were measured by specific marker reactions in human liver microsomes. Nine healthy male subjects genotyped for CYP2D6*1/*1 or *1/*2 were included in a randomized, open-label, three-treatment three-period, 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; treatment B), or after pretreatment of sarpogrelate for 3 days (100 mg tid.; treatment C). Plasma levels of metoprolol and α-hydroxymetoprolol were determined using a validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) method. Changes in heart rate and blood pressure were monitored as pharmacodynamic responses to metoprolol. Sarpogrelate potently and selectively inhibited CYP2D6-mediated dextromethorphan O-demethylation with an IC50 (Ki) value of 3.05 μM (1.24 μM), in a competitive manner. M-1 also markedly inhibited CYP2D6 activity; its inhibitory effect with an IC50 (Ki) value of 0.201 μM (0.120 μM) was more potent than that of sarpogrelate. Co-administration of sarpogrelate increased the area under the plasma concentration–time curve from time zero to the last measurement (AUCt) of metoprolol increased by 53% (geometric mean ratio [GMR], 1.53; 90% confidence interval [CI], 1.09–2.32) and by 51% (1.51; 1.04–2.30), respectively. Similar patterns were observed for the in…
author: 조, 두연
language: en
keywords: Sarpogrelate, CYP2D6 inhibition, Drug-Drug interaction, Metoprolol, Pharmacokinetics, Pharmacodynamics, CYP2D6 억제, 약물-약물 상호작용, 약동학, 약력학
date published: 2015-10-29T05:29:58Z
date modified: 2026-07-24T00:51:50Z
provider: Ajou University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Ajou University