Molecular basis of cardiovascular drug metabolism: implications for predicting clinically important drug interactions.

The recent withdrawal of the calcium antagonist mibefradil from the market in the United States has refocused attention on drug interactions that involve cardiovascular drugs.1 It is appropriate to ask whether pharmacokinetic drug interactions like this that pose substantial clinical risk can be predicted and/or prevented. We believe that if the appropriate information is obtained during drug development and effectively communicated to physicians, many episodes such as that involving mibefradil will be predicted and prevented. Many known pharmacokinetic drug interactions with the potential for either excessive drug exposure, effect, and toxicity or decreased drug exposure and loss of drug effect are associated with phase I drug biotransformations.2 In addition, the importance of P-glycoprotein–mediated drug transport is currently being appreciated.3