Drug Metabolism

The FDA recognizes the importance of reaction phenotyping and recommends procedures to identify which enzymes are involved in the metabolism of a drug candidate. This information can be used to evaluate the victim potential of the drug candidate.  Seldane® (terfenadine), Propulsid® (cisapride), Hismanal® (astemizole) and Baycol® (cerivastatin) were all withdrawn from the US market because they have a high victim potential. The first three caused QT prolongation when administered with drugs that inhibited their metabolism by CYP3A4, whereas the fourth drug caused rhabdomyolysis when its metabolism by CYP2C8 was inhibited by gemfibrozil glucuronidation.

XenoTech's scientists were among the first to realize the importance of using pharmacologically relevant concentrations in evaluating drug metabolism in vitro (see the lansoprazole example below). This important principle is now codified in the FDA's Guidance Document. This practice is important in determining the most likely metabolic pathway of a compound. The in vitro metabolism of a drug candidate can be dominated by a low-affinity, high-capacity enzyme (such as CYP3A4), whereas in vivo, its metabolism is determined by a high-affinity, low capacity enzyme (such as CYP2C19).

See also: Pearce RE, Rodrigues AD, Goldstein JA and Parkinson A. Identification of the human P450 enzymes involved in lansoprazole metabolism. J Pharmacol Exp Ther 277: 805-816, 1996.