Effect of chirality on pharmacokinetics and pharmacodynamics

The clinical importance of individual pharmacokinetic and pharmacodynamic differences among enantiomers is discussed. A number of mechanisms in the body can be stereoselective, among them first-pass metabolism, metabolic clearance, renal clearance, and protein and tissue binding. Differences in first-pass metabolism may cause differences in the ratio of plasma concentrations of enantiomers when a drug is given by the intravenous route compared with the oral route. Stereoisomers of a drug may be metabolized by two different enzyme systems, resulting in different rates of metabolic clearance; age and sex may also affect the rates of enzymatic metabolism of stereoisomers. Substantial differences in the protein binding of two enantiomers may result in a difference in their glomerular filtration rates. Two enantiomers may bind differently to protein or to other tissue receptor sites, resulting in differences in drug effects or distribution. There are no simple answers to questions regarding the pharmacokinetics of racemic drug mixtures and single enantiomers. The properties of enantiomers in each drug will have to be evaluated for their pharmacokinetic disposition and their therapeutic index.