Mikov Momir, Đanić Maja, Pavlović Nebojša, Stanimirov Bojan, Goločorbin-Kon Svetlana, Stankov Karmen, Al-Salami Hani
Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
Eur J Drug Metab Pharmacokinet. 2017 Dec;42(6):881-890. doi: 10.1007/s13318-017-0417-y.
Following the drug administration, patients are exposed not only to the parent drug itself, but also to the metabolites generated by drug-metabolizing enzymes. The role of drug metabolites in cytochrome P450 (CYP) inhibition and subsequent drug-drug interactions (DDIs) have recently become a topic of considerable interest and scientific debate. The list of metabolites that were found to significantly contribute to clinically relevant DDIs is constantly being expanded and reported in the literature. New strategies have been developed for better understanding how different metabolites of a drug candidate contribute to its pharmacokinetic properties and pharmacological as well as its toxicological effects. However, the testing of the role of metabolites in CYP inhibition is still not routinely performed during the process of drug development, although the evaluation of time-dependent CYP inhibition during the clinical candidate selection process may provide information on possible effects of metabolites in CYP inhibition. Due to large number of compounds to be tested in the early stages of drug discovery, the experimental approaches for assessment of CYP-mediated metabolic profiles are particularly resource demanding. Consequently, a large number of in silico or computational tools have been developed as useful complement to experimental approaches. In summary, circulating metabolites may be recognized as significant CYP inhibitors. Current data may suggest the need for an optimized effort to characterize the inhibitory potential of parent drugs metabolites on CYP, as well as the necessity to develop the advanced in vitro models that would allow a better quantitative predictive value of in vivo studies.
药物给药后，患者不仅会接触到母体药物本身，还会接触到药物代谢酶产生的代谢产物。药物代谢产物在细胞色素P450（CYP）抑制及随后的药物相互作用（DDIs）中的作用，最近已成为一个备受关注且引发科学争论的话题。被发现对临床相关药物相互作用有显著贡献的代谢产物清单在不断扩充，并在文献中有所报道。已开发出新策略，以更好地理解候选药物的不同代谢产物如何影响其药代动力学特性、药理作用以及毒理作用。然而，在药物研发过程中，仍未常规开展对代谢产物在CYP抑制中作用的测试，尽管在临床候选药物筛选过程中对时间依赖性CYP抑制的评估可能会提供有关代谢产物在CYP抑制中可能作用的信息。由于在药物发现的早期阶段需要测试大量化合物，评估CYP介导的代谢谱的实验方法对资源要求特别高。因此，已开发出大量计算机模拟或计算工具，作为实验方法的有益补充。总之，循环代谢产物可能被视为重要的CYP抑制剂。当前数据可能表明，需要做出优化努力来表征母体药物代谢产物对CYP的抑制潜力，以及开发先进的体外模型，以实现对体内研究更好的定量预测价值。
