Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption
Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption
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DOI：
10.1016/j.addr.2007.08.043
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发表时间：
2008-03-17
影响因子：
16.1
通讯作者：
Benet, Leslie Z.
中科院分区：
文献类型：
--
作者：
Custodio, Joseph M.;Wu, Chi-Yuan;Benet, Leslie Z.
预测药物处置的能力涉及同时考虑许多化学和生理变量，而食物对药物可利用度的速率和程度的影响由于胃肠道（GI）在餐后的变化而更加复杂。一种能够评估在有或无食物存在的情况下口服给药后多变量相互作用的系统，将极大地有益于药物开发的早期阶段。在当今大多数新分子实体都是高渗透性、难溶性、广泛代谢的化合物（BDDCS 2类）的时代，这一点尤其正确，由于转运体 - 酶相互作用的显著影响，这类化合物在确定转运体的影响方面呈现出最复杂的关系。本综述通过考虑吸收/转运/消除的相互作用来评估胃肠道管腔环境，并通过考虑溶解度、渗透性和代谢的重要性来评估理化性质问题。我们专注于BDDCS及其在预测药物处置方面的效用。此外，我们关注食物对药物可利用度（F）程度的影响，这似乎与高脂肪餐对转运体有显著抑制作用时所预期的情况密切相符。也就是说，高脂肪餐和脂质辅料对1类药物的F预计影响很小；它们会增加2类药物的F，而降低3类药物的F。（C）2007爱思唯尔B.V.保留所有权利。
The ability to predict drug disposition involves concurrent consideration of many chemical and physiological variables and the effect of food on the rate and extent of availability adds further complexity due to postprandial changes in the gastrointestinal (GI) tract. A system that allows for the assessment of the multivariate interplay occurring following administration of an oral dose, in the presence or absence of meal, would greatly benefit the early stages of drug development. This is particularly true in an era when the majority of new molecular entities are highly permeable, poorly Soluble, extensively metabolized compounds (BDDCS Class 2), which present the most complicated relationship in defining the impact of transporters due to the marked effects of transporter-enzyme interplay. This review evaluates the G1 luminal environment by taking into account the absorption/transport/elimination interplay and evaluates the physiochemical property issues by taking into account the importance of solubility, permeability and metabolism. We concentrate on the BDDCS and its utility in predicting drug disposition. Furthermore, we focus on the effect of food on the extent of drug availability (F), which appears to follow closely what might be expected if a significant effect of high fat meals is inhibition of transporters. That is, high fat meals and lipidic excipients would be expected to have little effect on F for Class I drugs; they would increase F of Class 2 drugs, while decreasing F for Class 3 drugs. (C) 2007 Elsevier B.V. All rights reserved.