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首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Physiologically based pharmacokinetics of cyclosporine A: reevaluation of dose-nonlinear kinetics in rats.
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Physiologically based pharmacokinetics of cyclosporine A: reevaluation of dose-nonlinear kinetics in rats.

机译：环孢霉素A的基于生理的药代动力学：大鼠非线性剂量动力学的重新评估。

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摘要

The disposition kinetics of Cyclosporine A (CyA) in rat, based on measurement in arterial blood, appeared dose-linear over a wide i.v. dose range (1.2-30 mg/kg). Physiologically based pharmacokinetic (PBPK) analysis, however, demonstrated that this was an apparent observation resulting from counterbalancing nonlinear factors, such as saturable blood and tissue distribution, as well as clearance (CLb). A PBPK model was successfully developed taking into account these multiple nonlinear factors. Tissue distribution was distinctly different among various organs, being best described by either a linear model (muscle, fat; Model 1), one involving instantaneous saturation (lung, heart, bone, skin, thymus; Model 2), noninstantaneous saturation (kidney, spleen, liver, gut; Model 3), or one with saturable efflux (brain; Model 4). Overall, the whole body volume of distribution at steady state for unbound CyA (Vuss) decreased with increasing dose, due at least in part to saturation of tissue-cellular cyclophilin binding. Clearance, essentially hepatic, and described by the well-stirred model, was also adequately characterized by Michaelis-Menten kinetics, Km 0.60 microgram/ml. In model-based simulations, both volume of distribution at steady state (Vss,b) and CLb varied in a similar manner with dose, such that terminal t1/2 remained apparently unchanged; these dose responses were attenuated by saturable blood binding. CyA concentration measured in arterial blood was not always directly proportional to the true exposure, i.e., unbound or target tissue concentrations. The PBPK model not only described comprehensively such complicated PK relationships but also permitted assessment of the sensitivity of individual parameters to variation in local nonlinear kinetics. Using this approach, dose-dependent CyA uptake into brain was shown to be sensitive to both active and passive transport processes, and not merely the affinity of the active (efflux) transporter at the level of the blood-brain barrier.
机译：根据在动脉血中的测量，在大鼠中环孢霉素A（CyA）的处置动力学在宽的静脉内呈剂量线性。剂量范围（1.2-30 mg / kg）。但是，基于生理学的药代动力学（PBPK）分析表明，这是由平衡非线性因素（如饱和血液和组织分布以及清除率（CLb））引起的明显观察结果。考虑到这些多个非线性因素，成功开发了PBPK模型。各个器官之间的组织分布明显不同，最好用线性模型（肌肉，脂肪;模型1），涉及瞬时饱和（肺，心脏，骨骼，皮肤，胸腺;模型2），非瞬时饱和（肾脏，脾，肝，肠;模型3）或具有饱和外排的模型（脑;模型4）。总体而言，未结合的CyA（Vuss）在稳态下的全身分布体积随剂量的增加而减少，这至少部分是由于组织细胞亲环蛋白结合的饱和所致。间隙，基本上是肝脏的，并由充分搅拌的模型描述，还通过Michaelis-Menten动力学Km 0.60微克/毫升充分表征。在基于模型的模拟中，稳态下的分布体积（Vss，b）和CLb随剂量的变化类似，因此t1 / 2末端显然保持不变;这些剂量反应因饱和血液结合而减弱。动脉血中测得的CyA浓度并不总是与真实暴露直接成正比，即未结合或目标组织的浓度。 PBPK模型不仅全面描述了这种复杂的PK关系，而且还允许评估单个参数对局部非线性动力学变化的敏感性。使用这种方法，剂量依赖性的CyA摄入脑对主动和被动转运过程均敏感，而不仅仅是主动（外排）转运蛋白在血脑屏障水平上的亲和力。

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