Pharmacological importance of stereochemical resolution of enantiomeric drugs.

Drug enantiomers have identical properties in an achiral environment, but should be considered as different chemical compounds. This is because they often differ considerably in potency, pharmacological activity and pharmacokinetic profile, since the modules with which they interact in biological systems are also optically active. Within biological systems, the metabolism of one isomer may be via a different pathway or occur at a different rate from that of the other isomer. Preferential binding of one isomer to plasma proteins may cause differences in circulating free drug and hence alter concentrations at active sites. Interactions of both isomers may differ at the active sites through which pharmacological action is mediated. Actions and levels of activity of the stereoisomers in vivo may also differ. All the pharmacological activity may reside in a single enantiomer, whereas several possibilities exist for the other enantiomer-- it may be inactive, have a qualitatively different effect, an antagonistic effect or produce greater toxicity. Two isomers may have nearly identical qualitative pharmacological activity, qualitatively similar pharmacological activity but quantitatively different potency, or qualitatively different pharmacological activity. To avoid adverse effects and optimise the therapeutic value of enantiomeric drugs, it is necessary that methods for the resolution of racemates be evolved and devolved to determine isomeric purity, establish the effectiveness of isomers of the drug, and detect the presence of an enantiomer with lower therapeutic activity and undesirable adverse effects. Even if a drug is given as a pure enantiomer, methods to discriminate between enantiomers are required because racemisation can occur both in vitro and in vivo. Methods developed for resolution of drug enantiomers should facilitate routine testing of single isomers and their metabolites, studies of pharmacological, toxicological and clinical effectiveness, routine analysis of racemates, pure enantiomers or intermediates in manufacturing processes, and investigation of the potential for inversion of an enantiopure drug substance during the early stages of drug development and therapeutic drug monitoring.