Population pharmacokinetics of mizoribine in adult recipients of renal transplantation
Population pharmacokinetics of mizoribine in adult recipients of renal transplantation
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DOI：
10.1007/s10157-011-0487-0
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发表时间：
2011-12-01
影响因子：
2.3
通讯作者：
Hashimoto, Yukiya
中科院分区：
文献类型：
--
作者：
Ishida, Kazuya;Okamoto, Masahiko;Hashimoto, Yukiya
采用非线性混合效应模型（nonlinear mixed effects model，NONMEM）对114例（男66例，女48例）肾移植受者口服咪唑立宾（25-450 mg/d）的药代动力学数据进行群体分析。肌酐清除率（CLcr）范围为7.6- 136.1mL/min，平均49.2mL/min，咪唑立宾在肾移植受者体内的药代动力学符合一级吸收一室模型。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0.983 h（-1）。将表观分布容积（V/F）建模为体重（WT）的函数，平均值估计为0.858 x WT L。将口服清除率（CL/F）建模为肌酐清除率（CLcr）的函数，平均值估计为1.80 x CLcr x 60/1000 L/h。此外，在成年受者中CLcr校正的CL/F和WT校正的V/F之间存在很强的相关性，表明咪唑立宾的生物利用度（F）存在很大的个体间变异性，本研究结果表明，不仅肾脏排泄率，而且咪唑立宾的肠道吸收程度是造成该药物个体间药代动力学变异性的原因。
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 (CLcr) 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 x WT L. Oral clearance (CL/F) was modeled as a function of creatinine clearance (CLcr), and the mean value was estimated to be 1.80 x CLcr x 60/1000 L/h. In addition, there was a strong correlation between CLcr-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.