Stereoselectivity in drug metabolism

Many chiral drugs are used as their racemic mixtures in clinical practice. Two enantiomers of a chiral drug generally differ in pharmacodynamic and/or pharmacokinetic properties as a consequence of the stereoselective interaction with optically active biological macromolecules. Thus, a stereospecific assay to discriminate between enantiomers is required in order to relate plasma concentrations to pharmacological effect of a chiral drug. Stereoselective metabolism of drugs is most commonly the major contributing factor to stereoselectivity in pharmacokinetics. Metabolizing enzymes often display a preference for one enantiomer of a chiral drug over the other, resulting in enantioselectivity. The structural characteristics of enzymes dictate the enantiomeric discrimination associated with the metabolism of chiral drugs. The stereoselectivity can, therefore, be viewed as the physical property characteristic that phenotypes the enzyme. This review provides a comprehensive appraisal of stereochemical aspects of drug metabolism (i.e., enantioselective metabolism and first-pass effect, enzyme-selective inhibition or induction and drug interaction, species differences and polymorphic metabolism).