Development of the theory of assessment for the therapeutic and adverse effect of drugs for the purpose of rational drug use

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Antiplatelet agents (cilostazol, sarpogrelate hydrochloride, aspirin, and ticlopidine) were investigated based on pharmacokinetics and pharmacodynamics. Cilostazol is a potent inhibitor of human platelet aggregation and selectively inhibits human platelet cyclic adenosine monophosphate phosphodiesterase type III.A pharmacokinetic-pharmacodynamic model for ascertaining the antiplatelet effect of cilostazol considering the reversible inhibition of phosphodiesterase in the platelet was developed. The estimated average inhibition of phosphodiesterase was 59.7% after oral administration of usual dose. A significant linear relationship between the calculated inhibitory effects on phosphodiesterase and inhibitory effects on collagen-induced platelet aggregation was obtained(p<0.05). Based on this finding, a new method for predicting inhibitory effects on collagen-induced platelet aggregation after oral administration of cilostazol was developed. Sarpogrelate and its active metabolite (M-1) ar … More e potent inhibitors of human platelet aggregation, selectively inhibit human platelet 5-HT_2-serotonergic receptor. A pharmacokinetic-pharmacodynamic model for ascertaining the antiplatelet effect of sarpogrelate and M-1, considering both the competitive reversible inhibition and the association/dissociation process of these drugs at the 5-HT_2 receptor in the platelet was developed. The developed model was well fitted to the actual data, and suggested that M-1 was more effective to the inhibition on platelet aggregation than sarpogrelate. Based on this finding, a new method was developed for predicting inhibitory effects on the platelet aggregation after oral administration of sarpogrelate hydrochloride. The relationship between plasma concentration of ticlopidine and its inhibitory effect on platelet aggregation in human was analyzed using a pharmacokinetic-pharmacodynamic model. Assuming that ticlopidine acts on platelet precursors in the bone marrow, the apparent reaction rate constant of ticlopidine and platelet precursors (K), apparent transformation rate constant of platelet precursors (kr) and apparent elimination rate constant of platelets (ke) were estimated. The antiaggregation effects of ticlopidine on platelets after administration of 100, 200 and 300 mg (b.i.d. for 8 days) were simulated using the pharmacokinetic-pharmacodynamic parameters of K, kr and ke. While the antiaggregation effect reached the steady state within 3-4 days without dose-dependency of the interval, the maximum effect increased with dose. The antiplatelet effects of aspirin (inhibition of thromboxane B_2 (TXB_2) production) after repeated administrations of 40, 80 and 320 mg/day for 8 days were simulated using these pharinacokinetic-pharmacodynamic parameters and compared with those of ticlopidine. The maximum inhibition was reached within 2 days after 40 mg administration of aspirin and even earlier (within 1 day) after 80 mg. The duration of inhibitory effect of aspirin on TBX_2 pThese pharmacokinetic-pharmacodynamic models may be useful for establishing the dosing regimen of antiplatelet drugs in clinical settings. Less