Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Clin Exp Nephrol. 2011 Dec;15(6):900-6. doi: 10.1007/s10157-011-0487-0. Epub 2011 Jul 14.
The aim of the present study was to estimate the population pharmacokinetic parameters of mizoribine in adult recipients of renal transplantation using a nonlinear mixed effects model (NONMEM) program.
Pharmacokinetic data for population analysis were retrospectively collected from 114 recipients (66 males and 48 females) routinely treated with oral administration of mizoribine (25-450 mg/day). The range of creatinine clearance (CL(cr)) was 7.6-136.1 mL/min (mean 49.2 mL/min).
The pharmacokinetics of mizoribine in adult recipients of renal transplantation was well described by a 1-compartment model with first-order absorption. The mean value of the absorption lag time (ALAG) and absorption rate constant (KA) was estimated to be 0.581 and 0.983 h(-1), respectively. Apparent volume of distribution (V/F) was modeled as a function of body weight (WT), and the mean value was estimated to be 0.858 × WT L. Oral clearance (CL/F) was modeled as a function of creatinine clearance (CL(cr)), and the mean value was estimated to be 1.80 × CL(cr) × 60/1000 L/h. In addition, there was a strong correlation between CL(cr)-corrected CL/F and WT-corrected V/F in the adult recipients, indicating large interindividual variability in bioavailability (F) of mizoribine.
The present findings suggested that not only the rate of renal excretion but also the extent of intestinal absorption of mizoribine is responsible for the large interindividual pharmacokinetic variability of the drug.
本研究旨在使用非线性混合效应模型（NONMEM）程序估算成人肾移植受者咪酯的群体药代动力学参数。
从 114 例（66 名男性和 48 名女性）常规接受咪酯（25-450mg/天）口服治疗的受者中回顾性收集群体分析药代动力学数据。肌酐清除率（CL（cr））范围为 7.6-136.1mL/min（平均 49.2mL/min）。
咪酯在成人肾移植受者中的药代动力学特征良好，可通过具有一级吸收的 1 室模型来描述。吸收滞后时间（ALAG）和吸收速率常数（KA）的平均值分别估计为 0.581 和 0.983h(-1)。表观分布容积（V/F）作为体重（WT）的函数进行建模，平均值估计为 0.858×WT L。口服清除率（CL/F）作为肌酐清除率（CL（cr））的函数进行建模，平均值估计为 1.80×CL（cr）×60/1000 L/h。此外，成人受者中 CL（cr）校正后的 CL/F 与 WT 校正后的 V/F 之间存在很强的相关性，表明咪酯的生物利用度（F）存在很大的个体间变异性。
本研究结果表明，咪酯的药代动力学个体间变异性大不仅与肾排泄率有关，还与肠道吸收程度有关。
