Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan.
Curr Drug Metab. 2010 Nov;11(9):793-805. doi: 10.2174/138920010794328904.
The bioavailability of therapeutic agents can be improved by using prodrugs which have better passive diffusion than the active agents. Intestinal hydrolysis is an important reaction in the bioconversion of prodrugs, and may be the rate-limiting factor in their absorption. Carboxylesterase (CES) is ubiquitous in most organs and is located in the endoplasmic reticulum. Single-pass perfusion experiments in rat intestine have shown that CES is the main enzyme involved in intestinal first-pass hydrolysis. In man, intestinal CESs belong to the CES2 gene family and their activity is nearly constant along the jejunum and ileum. The predominant human intestinal CES, hCE2, preferentially hydrolyzes prodrugs in which the alcohol group of a pharmacologically active molecule has been modified by the addition of a small acyl group. In preclinical animal models, CES2 isozymes are also the major intestinal enzymes although they have different substrate specificities to human CES2, while CES1 isozymes and other unidentified enzymes are also present. It is therefore difficult to predict human intestinal absorption from animal experiments. Caco-2 cells mainly express the human CES1 isozyme, hCE1, which shows quite different substrate specificity from hCE2, making Caco-2 cells unsuitable for prediction of human intestinal absorption of prodrugs. However, we have developed a novel experimental method for predicting the human intestinal absorption of prodrugs using Caco-2 cells in which CES-mediated hydrolysis has been inhibited. The expression of hCE2 shows inter-individual variation and is regulated by several mechanisms, such as gene polymorphism and epigenetic processes. There are no reports suggesting that severe toxicity is associated with prodrugs due to genetic polymorphism of the CES2 gene.
治疗药物的生物利用度可以通过使用前药来提高，前药比活性药物具有更好的被动扩散性。肠道水解是前药生物转化中的一个重要反应，可能是其吸收的限速因素。羧酸酯酶 (CES) 广泛存在于大多数器官中，位于内质网中。大鼠肠的单次通过灌注实验表明，CES 是参与肠道首过水解的主要酶。在人类中，肠 CES 属于 CES2 基因家族，其活性在空肠和回肠中几乎保持不变。主要的人类肠 CES，hCE2，优先水解药理学活性分子的醇基团被添加小酰基修饰的前药。在临床前动物模型中，CES2 同工酶也是主要的肠酶，尽管它们对人类 CES2 的底物特异性不同，而 CES1 同工酶和其他未识别的酶也存在。因此，很难从动物实验中预测人类肠道吸收。Caco-2 细胞主要表达人类 CES1 同工酶 hCE1，其底物特异性与 hCE2 有很大不同，这使得 Caco-2 细胞不适合预测前药的人类肠道吸收。然而，我们开发了一种使用 Caco-2 细胞预测前药的人类肠道吸收的新实验方法，其中 CES 介导的水解已被抑制。hCE2 的表达存在个体间差异，并受多种机制调节，如基因多态性和表观遗传过程。没有报道表明由于 CES2 基因的遗传多态性，前药会导致严重的毒性。
