Stereoselectivity: an issue of significant importance in clinical pharmacology

Many drugs have one or more asymmetric centers and are administered as a racemate containing an equal mixture of enantiomers with different pharmacologic properties, routes, and rates of disposition in humans. For example, S-warfarin is more potent than R-warfarin, and is metabolized by different pathways. The S-enantiomer is primarily oxidized, and the R-enantiomer is metabolized by both oxidation and reduction. Nevertheless, because of the difficulty in separating and analyzing individual enantiomers, most pharmacokinetic and pharmacodynamic studies on drugs have been performed without considering the stereochemical factors. This is unfortunate, because a nonstereoselective approach to the study of chiral drugs precludes insight into potential valuable information that may be relevant to drug development and evaluation. On the other hand, when the pharmacologic properties (including activity, disposition, and interaction with the other enantiomer) of enantiomers have been defined, manipulation of the enantiomeric ratio or use of the pure enantiomer can be pursued to optimize therapeutic efficacy.