Shibata Yoshihiro, Takahashi Hiroyuki, Chiba Masato, Ishii Yasuyuki
Drug Metabolism, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Ibaraki, Japan.
Drug Metab Dispos. 2002 Aug;30(8):892-6. doi: 10.1124/dmd.30.8.892.
A novel and convenient method was established for the prediction of in vivo metabolic clearance in human liver. The present method applied the in vitro-in vivo extrapolation paradigm previously established in rats to the in vitro data obtained from cryopreserved human hepatocytes. Predicted hepatic availability and clearance were compared with the reported oral bioavailability and plasma clearance in humans for 14 clinically used drugs (naloxone, buspirone, verapamil, lidocaine, imipramine, metoprolol, timolol, antipyrine, diazepam, quinidine, caffeine, propranolol, diclofenac, and phenacetin). A large interindividual variation was observed in the intrinsic metabolic clearance among separate cryopreserved preparations from different subjects. The prediction generally resulted in a marked underestimation when the biologically based scaling factor (3.1 x 10(9) cells/kg) was used for the extrapolation of in vitro data (milliliters per minutes per cells) to in vivo value (milliliters per minutes per kilograms). Reasonably good in vitro-in vivo correlations were obtained with empirically calculated scaling factors, 8.5 x 10(9) (cells/kg) from 10 individual preparations and 10.8 x 10(9) (cells/kg) from pooled preparation of two selected lots, which were 3- to 4-fold larger than the biologically based scaling factor. These data suggested that the calibration of inherent interindividual variation of metabolic activities among different cryopreserved preparations of human hepatocytes to obtain the empirical scaling factor, which is applicable only to the preparation used, was an essential step for more reliable and quantitative prediction of in vivo metabolic activity in humans.
建立了一种新颖且便捷的方法来预测人体肝脏中的体内代谢清除率。本方法将先前在大鼠中建立的体外-体内外推模式应用于从冷冻保存的人肝细胞获得的体外数据。将预测的肝脏可用性和清除率与14种临床使用药物（纳洛酮、丁螺环酮、维拉帕米、利多卡因、丙咪嗪、美托洛尔、噻吗洛尔、安替比林、地西泮、奎尼丁、咖啡因、普萘洛尔、双氯芬酸和非那西丁）在人体中的报告口服生物利用度和血浆清除率进行比较。在来自不同受试者的单独冷冻保存制剂中，观察到固有代谢清除率存在较大的个体间差异。当使用基于生物学的比例因子（3.1×10⁹细胞/千克）将体外数据（每分钟每细胞毫升数）外推至体内值（每分钟每千克毫升数）时，预测结果通常会明显低估。使用根据经验计算的比例因子可获得合理良好的体外-体内相关性，从10个单独制剂中计算得出的比例因子为8.5×10⁹（细胞/千克），从两个选定批次的混合制剂中计算得出的比例因子为10.8×10⁹（细胞/千克），这些比例因子比基于生物学的比例因子大3至4倍。这些数据表明，校准人肝细胞不同冷冻保存制剂之间代谢活性的固有个体间差异以获得仅适用于所用制剂的经验比例因子，是更可靠且定量预测人体体内代谢活性的关键步骤。
