Piekoszewski W, Chow F S, Jusko W J
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
Drug Metab Dispos. 1993 Jul-Aug;21(4):690-8.
Tacrolimus is a macrolide immunosuppressive drug undergoing clinical trials for organ transplantation. Whole animal studies were undertaken to assess the rabbit as an animal model for tacrolimus pharmacokinetics. The disposition of tacrolimus in rabbits following 0.5 mg/kg iv and 2.0 mg/kg po doses is similar to man. The apparent plasma clearance 1.67 liters/hr/kg is more than 5-fold higher than blood clearance 0.31 liters/hr/kg. The steady-state volume of distribution is 30.7 liters/kg for plasma and 6.3 liters/kg for whole blood. The bioavailability after oral administration calculated from plasma and whole blood is low with a mean value of 9.7%. The in vitro studies and fitting using a nonlinear red blood cell (RBC)-plasma binding/diffusion model showed slow diffusion of drug from RBC to plasma (t1/2 = 7 min, CLD = 0.085 ml/min). In perfused liver studies, the extraction ratio of tacrolimus from blood with hematocrit of 0.1 is low (0.20). However, extraction of drug from plasma is moderate (0.42), and plasma concentrations are elevated by an average of 28% because of redistribution of tacrolimus from RBC. This creates a lower apparent plasma clearance (DO/AUC) for equilibrated (30 min at 37 degrees C) samples (15.4 ml/min) compared with samples centrifuged within 5 min (22.1 ml/min). RBC efflux was accounted for using a comprehensive perfusion/diffusion model. The intrinsic metabolic clearance averaged 29.2 ml/min. Simulations showed that the apparent plasma clearance of tacrolimus is closely correlated with RBC binding capacity (whole blood:plasma ratio). Higher ratios caused greater apparent plasma clearance (lower concentration of tacrolimus in reservoir plasma) because strong binding of drug by erythrocytes prevents tacrolimus from diffusion into plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
他克莫司是一种正在进行器官移植临床试验的大环内酯类免疫抑制药物。开展了整体动物研究，以评估兔作为他克莫司药代动力学的动物模型。兔静脉注射0.5mg/kg和口服2.0mg/kg剂量后他克莫司的处置情况与人相似。表观血浆清除率为1.67升/小时/千克，比血液清除率0.31升/小时/千克高5倍多。血浆稳态分布容积为30.7升/千克，全血为6.3升/千克。根据血浆和全血计算，口服给药后的生物利用度较低，平均值为9.7%。体外研究以及使用非线性红细胞（RBC）-血浆结合/扩散模型进行拟合显示，药物从红细胞向血浆的扩散缓慢（t1/2 = 7分钟，CLD = 0.085毫升/分钟）。在肝脏灌注研究中，血细胞比容为0.1时他克莫司从血液中的提取率较低（0.20）。然而，药物从血浆中的提取率适中（0.42），由于他克莫司从红细胞的再分布，血浆浓度平均升高28%。这使得平衡（37℃30分钟）样品的表观血浆清除率（DO/AUC）（15.4毫升/分钟）低于5分钟内离心的样品（22.1毫升/分钟）。使用综合灌注/扩散模型解释了红细胞流出情况。内在代谢清除率平均为29.2毫升/分钟。模拟显示，他克莫司的表观血浆清除率与红细胞结合能力（全血：血浆比值）密切相关。较高的比值导致表观血浆清除率更高（储存血浆中他克莫司浓度更低），因为药物与红细胞的强烈结合阻止了他克莫司扩散到血浆中。（摘要截断于250字）
