Background:  Changes in the activity of drug-metabolizing enzymes and transporters can cause significant, and potentially harmful, drug interactions. Early in drug development, in vitro methods are commonly performed to assess the interaction potential of drugs. However, these techniques may not be clinically predictive, because of differences in drug concentrations at the enzyme or transporter site compared with what may be obtained in vivo with standard doses of drugs, and to the unpredictable relevance of investigating any enzyme or transporter in isolation of the whole body system. Phenotyping is a process by which the in vivo activity of these enzymes or transporters can be assessed. Phenotyping involves giving subjects single doses of drugs (or “probes”) that are handled by individual enzymes or transporters. These drugs or their metabolites are generally measured in blood or urine before and after a drug of interest is administered. The difference between these measures gives an indication of the interaction potential of the drug. The simultaneous administration of more than 1 probe to measure the activities of multiple enzymes and transporters is called a “cocktail study”. Although commonly used in drug development, debate remains as to the utility of this approach. 

Conclusions:  This overview will review current probes and cocktails for assessing drug-metabolizing enzyme and transporter activity, discuss their value in understanding and predicting antiretroviral drug interactions, and examine their application to patient care.