Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut 06340, USA.
J Med Chem. 2010 Feb 11;53(3):1098-108. doi: 10.1021/jm901371v.
Oral bioavailability (F) is a product of fraction absorbed (Fa), fraction escaping gut-wall elimination (Fg), and fraction escaping hepatic elimination (Fh). In this study, using a database comprised of Fa, Fg, Fh, and F values for 309 drugs in humans, an analysis of the interrelation of physicochemical properties and the individual parameters was carried out in order to define the physicochemical space for optimum human oral bioavailability. Trend analysis clearly indicated molecular weight (MW), ionization state, lipophilicity, polar descriptors, and free rotatable bonds (RB) influence bioavailability. These trends were due to a combination of effects of the properties on Fa and first-pass elimination (Fg and Fh). Higher MW significantly impacted Fa, while Fg and Fh decreased with increasing lipophilicity. Parabolic trends were observed for bioavailability with polar descriptors. Interestingly, RB has a negative effect on all three parameters, leading to its pronounced effect on bioavailability. In conclusion, physicochemical properties influence bioavailability with typically opposing effects on Fa and first-pass elimination. This analysis may provide a rational judgment on the physicochemical space to optimize oral bioavailability.
口服生物利用度（F）是吸收分数（Fa）、肠道壁消除分数（Fg）和肝脏消除分数（Fh）的乘积。在这项研究中，使用包含 309 个人类药物的 Fa、Fg、Fh 和 F 值的数据库，对理化性质和各个参数之间的相互关系进行了分析，以确定最佳人体口服生物利用度的理化空间。趋势分析清楚地表明，分子量（MW）、电离态、亲脂性、极性描述符和自由可旋转键（RB）影响生物利用度。这些趋势归因于这些性质对 Fa 和首过消除（Fg 和 Fh）的综合影响。较高的 MW 显著影响 Fa，而 Fg 和 Fh 随着亲脂性的增加而降低。生物利用度与极性描述符呈抛物线趋势。有趣的是，RB 对所有三个参数都有负面影响，这对生物利用度有显著影响。总之，理化性质影响生物利用度，对 Fa 和首过消除的影响通常相反。这种分析可以对优化口服生物利用度的理化空间进行合理判断。
