Intra- and/or inter-individual variability in drug response is mainly a result of either subtherapeutic
or supratherapeutic plasma levels of the active drugs and their metabolites, with this variability
mainly being influenced by differences in the rate of drug metabolism. Indeed, drug metabolism
is largely determined by genetic polymorphism in the CYP enzymes, which are responsible for approximately
85% of the drug metabolism process. However, this genetic heterogeneity can accurately
predict actual drug metabolizing capacity (oxidation phenotype) for some individuals: poor metabolizers
(PMs), who cannot produce the drug metabolizing enzymes, and 20% of ultra-rapid metabolizers.
According to EMA recommendations, phenotyping procedures for drug interaction studies and clinical
research are therefore required to obtain actual data on the main CYP enzymes. With this purpose, cocktail
phenotyping approaches give information on the activity of different CYPs in just one experiment.
In this review, the issues related to the phenotyping of the main CYP enzymes are reviewed, and the
current in vivo phenotyping cocktails are analysed: the sampling procedures, probe drugs utilized, analytical
techniques and main applications are also discussed.
Based on this analysis, a fully validated cocktail approach to measure the metabolic activity of the main
CYP enzymes and drug transporters is still required. This novel approach should fulfil certain conditions:
a faster and simpler analytical methodology to obtain information on several CYPs in one experiment,
minimal sample amounts, and minimal doses of optimal probe drugs.