In vivo modulation of CYP enzymes by quinidine and rifampin

Background: The metabolism of drugs and other xenobiotics is mediated by en zymes whose activities can be modulated by different compounds. The activit ies of these modulators have the potential to be used to optimize drug acti on, prevent toxicity, or identify the enzymes involved in a reaction. This approach requires that selective agents be used for specific enzymes. Howev er, selectivity of action has been poorly characterized in vivo. Methods: This study investigated the effect of 3 and 28 days of treatment w ith quinidine (200 mg daily) and rifampin (INN, rifampicin) (600 mg daily) on the activities of four cytochrome P450 enzymes and N-acetyltransferase i n 28 healthy young male volunteers divided into three groups with a cocktai l of drug probes used, including caffeine, mephenytoin, debrisoquin (INN, d ebrisoquine), and dapsone. Results: Quinidine selectively and almost completely inhibited the activity of CYP2D6 from day 3 through day 28 without affecting any other enzymes. R ifampin showed evidence of time-dependent induction of the activities of al l measured oxidative routes of metabolism but decreased the acetylation rat io in fast acetylators. The quinidine/rifampin combination resulted in sele ctive CYP2D6 inhibition and induction of all other enzymes evaluated over t his time period, suggesting that predictable complex interactions occur wit h the drug combination. Conclusions: These observations illustrate the value of simultaneous assess ment of the effect of modulators on the activities of multiple specific enz ymes with the drug cocktail approach.