Selective inhibition of cytochrome P450 2D6 by Sarpogrelate and its active metabolite, M-1, in human liver microsomes

Abstract

The present study was performed to evaluate the in vitro inhibitory potential of

sarpogrelate and its active metabolite, M-1, on the activities of nine human

cytochrome (CYP) isoforms. Using a cocktail assay, the effects of sarpogrelate on

nine CYP isoforms and M-1 were measured by specific marker reactions in human

liver microsomes. Sarpogrelate potently and selectively inhibited CYP2D6-mediated

dextromethorphan O-demethylation with an IC50 (Ki) value of 3.05 muM (1.24 muM),

in a competitive manner. M-1 also markedly inhibited CYP2D6 activity; its

inhibitory effect with an IC50 (Ki) value of 0.201 muM (0.120 muM) was more

potent than that of sarpogrelate, and was similarly potent as quinidine (Ki,

0.129 muM), a well-known typical CYP2D6 inhibitor. In addition, sarpogrelate and

M-1 strongly inhibited both CYP2D6-catalyzed bufuralol 1'-hydroxylation and

metoprolol alpha-hydroxylation activities. However, sarpogrelate and M-1 showed

no apparent inhibition of the other following eight CYPs: CYP1A2, CYP2A6, CYP2B6,

CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5. Upon 30-minute preincubation of

human liver microsomes with sarpogrelate or M-1 in the presence of NADPH, no

obvious shift in IC50 was observed in terms of inhibition of the nine CYP

activities, suggesting that sarpogrelate and M-1 are not time-dependent

inactivators. Sarpogrelate strongly inhibited the activity of CYP2D6 at

clinically relevant concentrations in human liver microsomes. These observations

suggest that sarpogrelate could have an effect on the metabolic clearance of

drugs possessing CYP2D6-catalyzed metabolism as a major clearance pathway,

thereby eliciting pharmacokinetic drug-drug interactions.