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首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Analysis of antiplatelet effect of ticlopidine in humans: modeling based on irreversible inhibition of platelet precursors in bone marrow.
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Analysis of antiplatelet effect of ticlopidine in humans: modeling based on irreversible inhibition of platelet precursors in bone marrow.

机译：噻氯匹定对人体的抗血小板作用分析：基于不可逆地抑制骨髓中血小板前体的建模。

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摘要

The relationship between plasma concentration of ticlopidine and its inhibitory effect on platelet aggregation in human was analyzed using a pharmacokinetic/pharmacodynamic (PK/PD) model. The data of plasma concentration and inhibitory effect on platelet aggregation were taken from the literature. A two-compartment open model was fitted to plasma ticlopidine concentrations. 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 estimated values +/- S.D. were 1.01 +/- 1.08 ml micrograms-1 hr-1 for K, 0.265 +/- 0.259 hr-1 for kr and 0.0747 +/- 0.0112 hr-1 for ke. The antiaggregation effects of ticlopidine on platelets after administration of 100, 200, and 300 mg (bid for 8 days) were simulated using the PD parameters of K, kr, and ke. While the antiaggregation effect reached steady state within 3-4 days without dose dependency of the interval, the maximum effect increased with dose. Furthermore, changing the elimination rate constant of ticlopidine from the central compartment in the model significantly changed the duration of inhibitory effect of ticlopidine on platelet aggregation. Therefore, the reported long duration of antiplatelet effect after discontinuation of ticlopidine, which is believed to be irreversible binding to the platelet, might have been partially caused by the delayed plasma elimination after a long therapy of ticlopidine. On the other hand, the mean life-span of platelets in the blood estimated by 1/ke after administration of ticlopidine was 14 hr, far below the life-span of platelets in the blood. For a more detailed analysis of the antiplatelet effect of ticlopidine, the possible contribution of reversible binding of the drug to glycoprotein IIb/IIIa should be considered in future PK/PD models.
机译：使用药代动力学/药效学（PK / PD）模型分析了噻氯匹定的血浆浓度与其对人体血小板聚集的抑制作用之间的关系。血浆浓度和对血小板聚集的抑制作用的数据来自文献。将两室开放模型拟合至血浆噻氯匹定浓度。假定噻氯匹定作用于骨髓中的血小板前体，估计了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）。估计值+/- S.D. K为1.01 +/- 1.08 ml微克-1 hr-1，kr为0.265 +/- 0.259 hr-1，ke为0.0747 +/- 0.0112 hr-1。使用K，kr和ke的PD参数模拟了噻氯匹定对100、200和300 mg（出价8天）给药后对血小板的抗聚集作用。虽然抗聚集作用在3-4天之内达到稳定状态，而没有间隔的剂量依赖性，但最大作用随剂量增加。此外，改变模型中噻氯匹定的消除速率常数可显着改变噻氯匹定对血小板聚集的抑制作用持续时间。因此，据报道，噻氯匹定停用后抗血小板作用的持续时间长，据信与血小板不可逆结合，这可能部分是由于长期服用噻氯匹定后延迟的血浆清除引起的。另一方面，噻氯匹定给药后，血液中血小板的平均寿命以1 / ke估算为14小时，远远低于血液中血小板的寿命。为了更详细地分析噻氯匹定的抗血小板作用，在将来的PK / PD模型中应考虑药物与糖蛋白IIb / IIIa可逆结合的可能贡献。

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