PHYSIOLOGICAL MODELING OF CYCLOSPORINE KINETICS IN RAT AND MAN
PHYSIOLOGICAL MODELING OF CYCLOSPORINE KINETICS IN RAT AND MAN
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DOI：
10.1007/bf01062191
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发表时间：
1991-02-01
期刊：
影响因子：
--
通讯作者：
ROWLAND, M
中科院分区：
文献类型：
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作者：
BERNAREGGI, A;ROWLAND, M
已经在大鼠中开发了环孢菌素的生理药代动力学模型，旨在预测血液、器官和组织中药物浓度的时间进程。 该模型假设组织分布受到灌注速率限制，并且每个组织充当充分搅拌的隔室。 未结合的平衡分布比以及未结合的分数和红细胞与血浆之间环孢菌素的分布等温线的值包含在描述每个组织中药物浓度的时间过程的速率方程中。 大鼠的参数值是通过连续输注研究通过实验获得的，其中通过渗透泵向两组大鼠中的每组大鼠皮下注射每天 2.7 和 13.9 mg/kg 剂量的环孢菌素，持续 6 天。 通过单克隆抗体 RIA 测定血液、脑脊液以及 18 个不同器官和组织中的稳态环孢菌素浓度。 一些组织中未结合平衡分配比值和未结合清除率的差异表明，分配和消除过程在测试的剂量率范围内可能具有非线性元素。 通过动力学实验对大鼠模型进行评估，其中在 15 分钟内静脉注射 6 mg/kg 剂量的环孢菌素，并测量血液浓度直至 56 小时。 灌注模型与动力学实验计算出的稳态（血液）分布体积 V(ss) 具有良好的一致性。 此外，血液浓度时间分布的模型预测与观察到的结果非常一致，除了在早期时刻外，此时血液中的分布速度比预测慢得多。 将模型扩展到人类时，预测的血浆浓度-时间曲线和 V(ss) 以及文献中的实验数据之间发现了良好的一致性。 大鼠和人类数据均表明，脂肪组织的分配在环孢菌素的药代动力学中起着重要作用。
A physiologic pharmacokinetic model of cyclosporin has been developed in the rat aimed at predicting the time course of drug concentrations in blood, organs, and tissues. The model assumes that tissue distribution is perfusion-rate limited and that each tissue acts as a well-stirred compartment. The unbound equilibrium distribution ratios as well as the values of the fraction unbound and the distributon isotherm of cyclosporin between erythrocytes and plasma are included in the rate equations describing the time course of the drug concentration in each tissue. Parameter values for the rat were obtained experimentally from a continuous infusion study, in which 2.7 and 13.9 mg/kg per day doses of cyclosporin were administered subcutaneously to each of two groups of rats by osmotic pumps for 6 days. Steady-state cyclosporin concentrations in blood, CSF, and 18 different organs and tissues, were determined by a monoclonal antibody RIA. Differences in values of the unbound equilibrium distribution ratios in some tissues and unbound clearance indicated that both the processes of distribution and elimination may have elements of nonlinearity over the range of dosing rates tested. The model was evaluated in the rat with a kinetic experiment in which a 6-mg/kg dose of cyclosporin was infused intravenously over 15 min, with measurements of blood concentrations until 56 hr. Good agreement was obtained for the volume of distribution at steady state (blood), V(ss), between the perfusion model and that calculated from the kinetic experiment. Also, the model prediction of the blood concentration temporal profile agreed closely with that observed except in the early moments, when distribution out of blood occurred considerably slower than predicted. On scaling the model up to humans, good agreement was found between the predicted plasma concentration-time profile and V(ss) and experimental data from the literature. Both rat and human data suggest that partition into adipose tissue plays an important role in the pharmacokinetics of cyclosporin.