CHIRALITY: PHARMACOKINETICS AND PHARMACODYNAMICS IN 3 DIMENSIONS

Abstract

1. Biological macromolecules are able to distinguish between enantiomeric substrates. A three‐point interaction between the drug enantiomers and the macromolecule (Easson‐Stedman hypothesis) can frequently account for this selectivity. 2. Significant pharmacodynamic differences between enantiomers are more the rule than the exception. 3. Pharmacokinetic differences between enantiomers are, in general, not as great as the pharmacodynamic differences. However, stereoselective protein binding, metabolism and renal clearance are still very important aspects of understanding drug disposition and the time course of drug action. 4. There may be pharmacokinetic and pharmacodynamic enantiomer‐enantiomer interactions. Consequently, the activity and disposition of a racemic drug may not be the simple sum of the activities and disposition of the individual enantiomers. 5. Enantiomers have been used as sensitive 3‐dimensional probes to establish structure‐activity relationships, to provide insights into genetic polymorphism of drug metabolism, and to provide insights into other aspects of drug disposition. 6. A need for a 3‐dimensional understanding of pharmacodynamics and pharma‐cokinetics is implicit in the asymmetric nature of biological environments.