Stereoselectivity in drug metabolism: molecular mechanisms and analytical methods

About 50% of therapeutic drugs are currently administered as a racemate, a mixture of equal proportions of two enantiomers. In an achiral environment, the enantiomers of a chiral drug show identical chemical and physical properties. However, they can present different chemical and pharmacological behavior in a chiral environment such as in the body. The interaction of two enantiomers with a chiral macromolecule, such as an enzyme or receptor, is three dimensional in nature, forming diastereomeric complexes resulting in a chiral recognition process. Moreover, when administered as a racemate, two enantiomers can display the pharmacokinetic processes (absorption, distribution, metabolism and excretion) in a stereoselective manner. Among these processes, stereoselectivity plays a central role in the metabolism due to the involvement of the enzymatic system. Thus, the purpose of the current review is to present important aspects related to stereochemistry of drug metabolism, with emphasis on molecular mechanisms involved in enzyme mediated reactions, such as those catalyzed by cytochrome P450, uridine 5'-diphospho (UDP)-glucuronosyltransferases and sulfotransferases. Additionally, recent advances regarding the analysis of chiral drugs and their metabolites employing different analytical techniques (high-performance liquid chromatography-HPLC and capillary electrophoresis-CE) will also be outlined.