Use of Cocktail Probe Drugs for Indexing Cytochrome P450 Enzymes in Clinical Pharmacology Studies - Review of Case Studies

Abstract

Background: 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.

Objective: 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.

Method: 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.

Results: 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.

Conclusion: 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.

Keywords: CYP enzymes; Cocktail probe drugs; clinical pharmacology; cytochrome P450; perpetrator capacity; pittsburg cocktail..