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

基于药代动力学和药效学研究了抗血小板药物（西洛他唑、盐酸沙泊格雷酯、阿司匹林和噻氯匹定）。西洛他唑是一种有效的人血小板聚集抑制剂，选择性抑制人血小板环腺苷单磷酸磷酸二酯酶III型。建立了考虑血小板磷酸二酯酶可逆性抑制的西洛他唑抗血小板作用的药代动力学-药效学模型。口服常规剂量后对磷酸二酯酶的平均抑制率为59.7%。对磷酸二酯酶的抑制作用与对胶原诱导的血小板聚集的抑制作用之间存在显著的线性关系（p<0.05）。基于这一发现，我们开发了一种新的方法来预测口服西洛他唑对胶原诱导的血小板聚集的抑制作用。马尾酸酯及其活性代谢物（M-1）是较强的人血小板聚集抑制剂，可选择性抑制人血小板5- ht_2 - 5-羟色胺能受体。在考虑竞争性可逆抑制和血小板中5-HT_2受体的结合/解离过程的情况下，建立了沙匹酸盐和M-1抗血小板作用的药代动力学-药效学模型。所建立的模型与实际数据拟合较好，表明M-1对血小板聚集的抑制作用比马尾酸盐更有效。基于这一发现，我们开发了一种新的方法来预测口服盐酸沙格雷酸酯对血小板聚集的抑制作用。采用药动学-药效学模型分析噻氯匹定血药浓度与其抑制血小板聚集作用的关系。假设噻氯匹定作用于骨髓内的血小板前体，估计噻氯匹定与血小板前体的表观反应速率常数(K)、血小板前体的表观转化速率常数（kr）和血小板的表观消除速率常数（ke）。采用药动学-药效学参数K、kr、ke模拟噻氯匹定在100mg、200mg、300mg（每日8 d）给药后对血小板的抗聚集作用。抗聚集作用在3 ~ 4天内达到稳定状态，无剂量依赖性，最大作用随剂量增加而增加。用这些药代动力学-药效学参数模拟阿司匹林40,80,320 mg/d连续8 d的抗血小板作用（抑制血栓素B_2 （TXB_2）的产生），并与噻氯匹定进行比较。服用40mg阿司匹林后2天内达到最大抑制，服用80mg后更早（1天内）达到最大抑制。阿司匹林对TBX_2抑制作用的持续时间，这些药动学-药效学模型可用于临床抗血小板药物给药方案的建立。少

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