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

Abstract

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 Major improvements in the scientific tools available to study cytochrome P-450 (CYP)–mediated biotransformations over the past decade4 now permit prediction of potential drug interactions during drug development. In some cases, these tools can be used to determine which of a series of drug candidates should undergo clinical development. They can also be used to understand and identify interactions between drugs that are in clinical use. An important component of this understanding is the challenge to determine the patient risk associated with each potential drug interaction because many pharmacokinetic drug interactions have no meaningful clinical consequence.5 The CYP family of enzymes, located in the liver and gastrointestinal tract, is the major source of catalytic activity for drug oxidation in humans.6 This enzyme family consists of >30 isoforms, but only a few have importance in human drug metabolism. This immensely simplifies the understanding of the system for prescribers. Briefly, naming of the CYP enzymes includes designation of the family, subfamily, and gene so that CYP 1(family), A(subfamily), 2(gene) designates the CYP isoform most associated with theophylline biotransformation. …