塩酸サルポグレラートによる血小板凝集抑制作用の速度論的解析とその処方設計への応用 : 未変化体及び活性代謝物(M-1)の血小板膜上5-HT_2受容体への可逆的阻害を考慮したPK/PDモデルの構築

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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-HT_2-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-HT_2 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.
社団法人日本薬学会の論文
1999-11-01

塩酸サルポグレラートによる血小板凝集抑制作用の速度論的解析とその処方設計への応用 : 未変化体及び活性代謝物(M-1)の血小板膜上5-HT_2受容体への可逆的阻害を考慮したPK/PDモデルの構築

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