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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Physiologically based pharmacokinetics of cyclosporine A: extension to tissue distribution kinetics in rats and scale-up to human.
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Physiologically based pharmacokinetics of cyclosporine A: extension to tissue distribution kinetics in rats and scale-up to human.

机译：环孢素A的基于生理学的药代动力学：扩展至大鼠的组织分布动力学，并扩大至人体。

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摘要

The tissue distribution kinetics of i.v. Cyclosporine A (CyA) was investigated extensively in rats. The concentration-to-time data of 11 organs were analyzed separately using local physiologically based pharmacokinetic models, involving nonlinear plasma-to-blood cell distribution, membrane-permeability-limited plasma-to-tissue distribution and either linear or nonlinear tissue binding. Two global physiologically based pharmacokinetic models were then evaluated, each comprising arterial and venous pools together with the 11 organs, adopting either of the two local models. Both global models successfully described the blood and tissue distribution kinetics of CyA. In nonlinear model, the estimated dissociation constants (Kd) for the intracellular saturable binding ranged 0.2 to 60 ng/ml among the organs, which are comparable with values reported for cyclophilin-CyA binding in vitro. The predicted human pharmacokinetic profile using the physiologically based pharmacokinetic models, after scale-up of physiological parameters from rat to human, generally agreed with the observations following i.v. and oral administration, with moderate discrepancies due presumably to uncharacterized species differences and/or the effect of i.v. vehicle on the CyA binding in plasma. Nevertheless, the models allow reasonable prediction of drug exposure at the biological target, i.e., intracellular, unbound CyA, which may differ among various organs according to the local physiological elements, e.g., tissue cellular membrane permeability. As well as helping optimize the CyA regimen in patients, who are likely to exhibit a variety of physiological and pathological conditions, the modeling suggests possible insights into the known grafted-organ specific efficacy of CyA.
机译：i.v.的组织分布动力学在大鼠中广泛研究了环孢菌素A（CyA）。使用基于局部生理学的药代动力学模型分别分析了11种器官的浓度-时间数据，包括非线性血浆到血液细胞分布，膜通透性受限的血浆到组织分布以及线性或非线性组织结合。然后评估了两个基于全局生理学的药代动力学模型，每个模型都包含动脉和静脉池以及11个器官，并采用两个局部模型之一。这两个全局模型成功地描述了CyA的血液和组织分布动力学。在非线性模型中，器官中细胞内可饱和结合的估计解离常数（Kd）在0.2至60 ng / ml之间，与报道的亲环蛋白CyA体外结合值相当。在将生理参数从大鼠放大到人类后，使用基于生理学的药代动力学模型预测的人的药代动力学概况通常与静脉注射后的观察结果一致。口服和口服给药，大概是由于未表征的物种差异和/或静脉内注射的作用引起的中等差异。载体对血浆中CyA的结合。然而，这些模型允许合理地预测药物在生物靶标上的暴露，即细胞内未结合的CyA，其根据局部生理因素（例如组织细胞膜通透性）在各个器官之间可能不同。该模型不仅有助于优化可能表现出多种生理和病理状况的患者的CyA方案，而且还暗示了对已知的CyA移植器官特异性功效的可能见解。

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