Tehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Department of Toxicology and Pharmacology, Tehran, Iran.
Expert Opin Drug Metab Toxicol. 2012 Oct;8(10):1231-45. doi: 10.1517/17425255.2012.698610. Epub 2012 Jul 7.
ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling is an important aspect of all drug developments. The pharmaceutical industry must always consider ADMET properties in order to optimize drug candidates and to introduce new formulations against existing marketed drugs. Consequently, candidate drug development may be halted early in the discovery phase or during the more costly drug development process because of their poor ADMET properties.
The main focus of this article is ADMET profiling, pharmacokinetic (PK) drug interactions, mechanisms and possible adverse drug reactions (ADRs) for approved phosphodiesterase-5 inhibitors (PDE5Is). The authors also look at the efficacy and non-erectogenic benefits of current PDE5Is, which are widely used by patients with erectile dysfunction (ED). The authors also discuss other unapproved PDE5Is such as aildenafil and udenafil, which are currently in use in clinical trials.
The authors believe that the enhancing effect of PDE5Is on the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway means that PDE5Is could be used to treat various conditions. An important issue in their development is 'cross-talk' between PDE5 and other PDEs and thus their specificity for other PDEs. But while it might be difficult to achieve the ideal ADMET profile, it should not necessarily prevent further development of a lead PDE5I. The risk assessment of PDE5Is, with respect to their ADMET properties, is therefore very important for predicting drug-drug interactions, possible side effects, ADRs and its future clinical applications.
药物的吸收、分布、代谢、排泄和毒性（ADMET）概况是所有药物开发的一个重要方面。制药行业必须始终考虑 ADMET 特性，以优化候选药物，并针对现有上市药物推出新的制剂。因此，候选药物的开发可能会在发现阶段早期或在成本更高的药物开发过程中因为其较差的 ADMET 特性而被停止。
本文的主要重点是 ADMET 概况、药代动力学（PK）药物相互作用、机制和已批准的磷酸二酯酶-5 抑制剂（PDE5Is）的可能不良反应（ADRs）。作者还研究了目前广泛用于勃起功能障碍（ED）患者的 PDE5Is 的疗效和非勃起治疗益处。作者还讨论了其他未批准的 PDE5Is，如阿伐那非和乌地那非，它们目前正在临床试验中使用。
作者认为，PDE5Is 对一氧化氮（NO）/环鸟苷单磷酸（cGMP）途径的增强作用意味着 PDE5Is 可用于治疗各种疾病。在其开发中一个重要问题是 PDE5 和其他 PDE 之间的“串扰”，因此它们对其他 PDE 的特异性。尽管可能难以实现理想的 ADMET 概况，但这并不一定阻止进一步开发主导 PDE5I。因此，对 PDE5Is 的风险评估，就其 ADMET 特性而言，对于预测药物-药物相互作用、可能的副作用、ADRs 及其未来的临床应用非常重要。
