Lau Yan Yi, Krishna Gopal, Yumibe Nathan P, Grotz Diane E, Sapidou Elpida, Norton Laura, Chu Inhou, Chen Cliff, Soares A D, Lin Chin-Chung
Schering-Plough Research Institute, Drug Metabolism and Pharmacokinetics, Kenilworth, New Jersey 07033, USA.
Pharm Res. 2002 Nov;19(11):1606-10. doi: 10.1023/a:1020765025857.
The in vivo hepatic extraction ratio of cynomolgus monkeys was correlated with the corresponding in vitro extraction ratios that were determined in monkey microsomal incubations.
For compounds that are eliminated mainly through liver phase I metabolism, the extraction ratio calculated from liver microsomal stability studies should correlate with their in vivo hepatic extraction ratios and also with their oral bioavailability in monkey. We used both well-stirred and parallel tube models of intrinsic clearance for the correlation. We also calculated extraction ratios for compounds within a given therapeutic area from fraction absorbed values that were estimated from the Caco-2 absorption model.
The present data show that in vitro extraction ratios in monkey microsomes are predictive of the in vivo hepatic extraction ratios in monkeys. All compounds with high extraction ratio (>70%) in vivo were successfully classified as high-extraction-ratio compounds based on the in vitro monkey microsomal stability data. From the results of this study, it appears that the parallel tube model provided a slightly better classification than the well-stirred model. CONCULUSIONS: The present method appears to be a valuable tool to rapidly screen and prioritize compounds with respect to liver first-pass metabolism in monkeys at an early phase of drug discovery.
将食蟹猴体内肝脏提取率与在猴微粒体孵育中测定的相应体外提取率相关联。
对于主要通过肝脏I相代谢消除的化合物，由肝脏微粒体稳定性研究计算得到的提取率应与其体内肝脏提取率以及在猴体内的口服生物利用度相关。我们使用了内在清除率的充分搅拌模型和平行管模型进行相关性分析。我们还根据从Caco-2吸收模型估算的吸收分数值计算了给定治疗领域内化合物的提取率。
目前的数据表明，猴微粒体中的体外提取率可预测猴体内的肝脏提取率。根据体外猴微粒体稳定性数据，所有体内提取率高（>70%）的化合物均成功归类为高提取率化合物。从本研究结果来看，平行管模型的分类效果似乎略优于充分搅拌模型。
本方法似乎是在药物发现早期阶段快速筛选化合物并根据肝脏首过代谢对其进行优先级排序的有价值工具。
