title: [Pharmacokinetic analysis of antiplatelet effect of sarpogrelate hydrochloride and its application to drug dosage regimen--modeling based on reversible inhibition of 5-HT2 serotonergic receptor in the platelet membrane by sarpogrelate hydrochloride and its metabolite].
abstract: Sarpogrelate hydrochloride is an antiplatelet drug, and expected to be useful in the treatment of chronic arterial occlusive diseases. Sarpogrelate and its active metabolite (M-1) are potent inhibitors of human platelet aggregation, and selectively inhibit 5-HT2-serotonergic receptors on human platelets. However, the plasma concentrations of these inhibitors do not correlate to the inhibitory effect on platelet aggregation after administration. Sarpogrelate disappears from the plasma more rapidly in comparison to the duration of its pharmacological effect, and the plasma concentration of M-1 is very low (< 1/10 of sarpogrelate). In this paper, we describe a pharmacokinetic-pharmacodynamic model for ascertaining the antiplatelet effects of sarpogrelate and M-1, by considering both the competitive reversible inhibition and the association/dissociation process of these drugs at the 5-HT2 receptors on platelets (Most data used for analysis were obtained from the literatures, except for the serum protein binding rate of M-1). The developed model was well fitted to the actual data, and suggested that M-1 was more effective for the inhibition of platelet aggregation than sarpogrelate. On the basis of these findings, a new method was developed for predicting inhibitory effects on platelet aggregation after oral administration of sarpogrelate hydrochloride. This method is useful for planning a rational dosage regimen of sarpogrelate hydrochloride and predicting the duration of antiplatelet activity after the discontinuance of the drug.
authors.affiliation: Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shimizu
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: A
authors.initials: A
authors.lastname: Tashita
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Kotaki
authors.forename: Y
authors.initials: Y
authors.lastname: Sawada
authors.forename: T
authors.initials: T
authors.lastname: Iga
mesh_terms: D000284:Administration, Oral; D001667:Binding, Competitive; D001792:Blood Platelets / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D008954:Models, Biological; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013386:Succinates / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D010975:Platelet Aggregation Inhibitors; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013386:Succinates; C064294:sarpogrelate; D012701:Serotonin