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Sarpogrelate hydrochloride의 CYP2D6 억제 효과와 약물-약물 상호작용 : CYP2D6 Inhibitory Activities of Sarpogrelate hydrochloride and Drug-Drug Interaction

초록/요약

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 increase in Cmax of metoprolol induced by sarpogrelate. However, the pharmacodynamics of metoprolol did not differ significantly among the three treatment groups. Sarpogrelate and M-1 were potent and selective competitive inhibitors of CYP2D6 in vitro. Especially, inhibition of CYP2D6 by M-1 was ten-fold more potent than that of sarpogrelate. Sarpogrelate weakly inhibited a sensitive CYP2D6 substrate, metoprolol, by increasing metoprolol exposure by less than two-fold, but sarpogrelate had few effects on the pharmacodynamics of metoprolol. Higher systemic exposure to metoprolol if co-administered with sarpogrelate is not expected to be clinically meaningful. Extrapolation of these results to clinical practice suggests that no special monitoring is necessary if administering sarpogrelate with sensitive CYP2D6 substrates.

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목차

Ⅰ. INTRODUCTION 1
Ⅱ. MATERIALS AND METHODS 4
A. CYP isoforms inhibition study 4
1. Chemicals and Reagents 4
2. Screening of Reversible Inhibitory Effects of Sarpogrelate and M-1 5
3. Determination of the Ki of Sarpogrelate and M-1 for CYP2D6 6
4. Time-Dependent Inhibitory Effects of Sarpogrelate and M-1 6
5. LC-MS/MS Analyses 7
6. Data Analyses 8
B. Pharmacokinetics of metoprolol associated with CYP2D6 genotypes 9
1. Subjects and Study design 9
2. Pharmacokinetics and Data Analysis 9
C. Effect of Sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol 10
1. Subjects 10
2. Determination of CYP2D6 genotypes 11
3. Study Design 12
4. Sample collection 13
5. Bioanalytical methods 14
6. Pharmacokinetic and Pharmacodynamic Assessments 15
7. Statistical Analyses 15
Ⅲ. RESULTS 17
Ⅳ. DISCUSSION 34
Ⅴ. CONCLUSION 37
REFERENCES 38
국문요약 45

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