Matsunaga N, Nishijima T, Hattori K, Iizasa H, Yamamoto K, Kizu J, Takanaka A, Morikawa A, Nakashima E
Department of Pharmaceutics, Kyoritsu College of Pharmacy, Tokyo, Japan.
Biol Pharm Bull. 2001 Nov;24(11):1305-10. doi: 10.1248/bpb.24.1305.
Previous reports have shown that the determination of drug metabolism capacity can be made by the pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test), in which an apparent liver-to-blood free concentration gradient in vivo (qg) is introduced, which is useful for evaluating fluctuations of CYPIA2 in rats. The aim of the present study was to examine the application of the PKCYP-test to evaluate the quantity of in vivo CYP2C11 by using tolbutamide as a probe, to confirm its validity using a physiologically-based pharmacokinetic rat model. Rats treated with carbon tetrachloride (CCl4-treated rats) were used as a model for low levels of CYP2C11 in the liver. In CCl4-treated rats, the total body clearance (CLtot) of tolbutamide and the amount of CYP2C11 fell to about a quarter and a third of that in control rats, respectively. The time-course of tolbutamide concentrations in serum in control rats could be simulated by a physiologically-based pharmacokinetic model. In CCl4-treated rats, take into consideration the qg value of control rats, the level of CYP2C11 was accurately predicted by the PKCYP-test, and the time-course of tolbutamide concentrations in serum could be predicted by the same physiologically-based pharmacokinetic model. In conclusion, we have shown that the PKCYP-test can be used to predict levels of CYP2C11. It was also demonstrated that the qg and amount of CYP are useful parameters in the PKCYP-test by constructing a physiologically-based pharmacokinetic model which was applied to the PKCYP-test.
以往的报告表明，可以通过体内细胞色素P450（CYP）量的药代动力学估计（PKCYP试验）来确定药物代谢能力，该试验引入了体内肝脏与血液的游离浓度梯度（qg），这对于评估大鼠体内CYPIA2的波动很有用。本研究的目的是通过使用甲苯磺丁脲作为探针，检验PKCYP试验在评估体内CYP2C11量方面的应用，并使用基于生理的大鼠药代动力学模型来确认其有效性。用四氯化碳处理的大鼠（CCl4处理大鼠）用作肝脏中CYP2C11水平较低的模型。在CCl4处理的大鼠中，甲苯磺丁脲的总体清除率（CLtot）和CYP2C11的量分别降至对照大鼠的约四分之一和三分之一。对照大鼠血清中甲苯磺丁脲浓度的时间进程可以用基于生理的药代动力学模型进行模拟。在CCl4处理的大鼠中，考虑到对照大鼠的qg值，PKCYP试验准确预测了CYP2C11的水平，并且血清中甲苯磺丁脲浓度的时间进程可以用相同的基于生理的药代动力学模型进行预测。总之，我们已经表明PKCYP试验可用于预测CYP2C11的水平。通过构建应用于PKCYP试验的基于生理的药代动力学模型，还证明了qg和CYP量是PKCYP试验中的有用参数。
