School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Pharmacol Rev. 2011 Sep;63(3):750-71. doi: 10.1124/pr.110.003459. Epub 2011 Jul 7.
The prodrug concept has been used to improve undesirable properties of drugs since the late 19th century, although it was only at the end of the 1950s that the actual term prodrug was introduced for the first time. Prodrugs are inactive, bioreversible derivatives of active drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then elicit its desired pharmacological effect in the body. In most cases, prodrugs are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the active parent drug. However, some prodrugs lack an obvious carrier or promoiety but instead result from a molecular modification of the prodrug itself, which generates a new active compound. Numerous prodrugs designed to overcome formulation, delivery, and toxicity barriers to drug utilization have reached the market. In fact, approximately 20% of all small molecular drugs approved during the period 2000 to 2008 were prodrugs. Although the development of a prodrug can be very challenging, the prodrug approach represents a feasible way to improve the erratic properties of investigational drugs or drugs already on the market. This review introduces in depth the rationale behind the use of the prodrug approach from past to present, and also considers the possible problems that can arise from inadequate activation of prodrugs.
前体药物概念自 19 世纪后期以来就被用于改善药物的不良性质，尽管直到 20 世纪 50 年代末期才首次引入前体药物这一术语。前体药物是指活性药物分子的无活性、生物可逆衍生物，必须在体内经历酶和/或化学转化才能释放出活性母体药物，然后该母体药物才能在体内发挥其所需的药理作用。在大多数情况下，前体药物是简单的化学衍生物，与活性母体药物仅相差一个或两个化学或酶步骤。然而，有些前体药物缺乏明显的载体或促进基团，而是通过前体药物本身的分子修饰产生新的活性化合物。许多旨在克服药物利用的制剂、传递和毒性障碍的前体药物已经上市。事实上，在 2000 年至 2008 年期间批准的所有小分子药物中，约有 20%是前体药物。尽管前体药物的开发可能极具挑战性，但前体药物方法代表了一种可行的方法，可以改善研究药物或已上市药物的不稳定性质。本文深入介绍了前体药物方法从过去到现在的应用原理，还考虑了前体药物激活不足可能带来的问题。
