Giri Poonam, Patel Harilal, Srinivas Nuggehally R
Department of Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Sarkhej-Bavla N.H. No. 8A, Moraiya. Tal: Sanand, Ahmedabad-382 210, India.
Suramus Bio, Drug Development, J.P. Nagar First Phase, Bangalore 560078, India.
Drug Metab Lett. 2019;13(1):3-18. doi: 10.2174/1872312812666181119154734.
The cocktail approach of probing drug metabolizing enzymes, in particular cytochrome P450 (CYP) enzymes, is a cornerstone in clinical pharmacology studies. The first report of the famous "Pittsburg cocktail" has led the way for the availability of numerous cocktail substrate mixtures that provide options for indexing of CYP enzymes and/or evaluating the perpetrator capacity of the drug.
The key objectives were: 1) To collate, tabulate, and discuss the various cocktail substrates to determine specific CYP enzyme activity in clinical pharmacology studies with specific case studies; 2) To introspect on how the cocktail approach has withstood the test of time and evolved for enabling key decision(s); 3) To provide some futuristic views on the use of cocktail in drug discovery and development.
The review was compiled after consultation with databases such as PubMed (NCBI database) and Google scholar to source various published literature on cocktail approaches in drug development.
In the reviewed case studies, CYP indexing was achieved using a single time point (differing for specific CYP enzyme) plasma determination of the metabolite to parent ratio for all CYP enzymes with the exception of CYP3A4/5, where multiple time points were required for exposure measurement of midazolam and its metabolite. Likewise, a single void of urine, for a specific time duration, has been utilized for the recovery measurements of parent and metabolite for CYP indexing purposes.
The review provides a comprehensive list of various types of cocktail approaches and discusses some key considerations including the evolution of the cocktail approaches over time, perspectives and futuristic views for the use of probe drugs to aid the execution of clinical pharmacology studies and data interpretation.
探究药物代谢酶，特别是细胞色素P450（CYP）酶的鸡尾酒法，是临床药理学研究的基石。著名的“匹兹堡鸡尾酒”的首次报道为众多鸡尾酒底物混合物的出现铺平了道路，这些混合物为CYP酶的索引和/或评估药物的肇事能力提供了选择。
主要目标如下：1）整理、列表并讨论各种鸡尾酒底物，通过具体案例研究确定临床药理学研究中特定CYP酶的活性；2）反思鸡尾酒法如何经受住时间的考验并不断演变以促成关键决策；3）对鸡尾酒法在药物发现和开发中的应用提供一些前瞻性观点。
通过咨询诸如PubMed（NCBI数据库）和谷歌学术等数据库来编写本综述，以获取有关药物开发中鸡尾酒法的各种已发表文献。
在 reviewed 的案例研究中，除CYP3A4/5外，所有CYP酶均通过在单个时间点（特定CYP酶有所不同）测定血浆中代谢物与母体的比例来实现CYP索引，对于CYP3A4/5，需要多个时间点来测量咪达唑仑及其代谢物的暴露量。同样，在特定时间段内收集的单次晨尿已被用于CYP索引目的的母体和代谢物回收率测量。
本综述提供了各种类型鸡尾酒法的综合列表，并讨论了一些关键考虑因素，包括鸡尾酒法随时间的演变、使用探针药物辅助临床药理学研究的执行和数据解释的观点及前瞻性看法。
