Physicochemical Space for Optimum Oral Bioavailability: Contribution of Human Intestinal Absorption and First-Pass Elimination
Physicochemical Space for Optimum Oral Bioavailability: Contribution of Human Intestinal Absorption and First-Pass Elimination
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DOI：
10.1021/jm901371v
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发表时间：
2010-02-11
影响因子：
7.3
通讯作者：
Troutman, Matthew D.
中科院分区：
文献类型：
--
作者：
Varma, Manthena V. S.;Obach, R. Scott;Troutman, Matthew D.
口服生物利用度（F）是吸收分数（Fa）、逃避肠壁消除分数（Fg）和逃避肝脏消除分数（Fh）的乘积。在这项研究中，使用的数据库组成的Fa，Fg，Fh和F值的309种药物在人体内，进行了分析的理化性质和各个参数的相互关系，以确定最佳的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），电离状态，亲油性，极性描述符，和自由旋转键（RB）影响生物利用度。这些趋势是由于特性对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。使用极性描述符观察到生物利用度的抛物线趋势。有趣的是，RB对所有三个参数都有负面影响，导致其对生物利用度的显著影响。总之，理化性质影响生物利用度，对Fa和首过消除的作用通常相反。该分析可为优化口服生物利用度的理化空间提供合理判断。
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.