Stereochemistry in Pharmacotherapy: When Mirror Images are Not Identical

Abstract

Objective: To describe how drug stereoisomers may differ in pharmacokinetic and pharmacodynamic properties and how these differences may affect therapeutic outcomes. Study Selection: Representative studies were chosen from the drug literature demonstrating stereoisomeric differences in drug absorption, protein binding and distribution, metabolism, and elimination. Furthermore, examples of pharmacodynamic differences between drug stereoisomers are presented to demonstrate that these stereoisomers not only may differ in pharmacologic potency, but may possess entirely different pharmacologic actions. Data Synthesis: Examples are presented demonstrating that when stereoisomeric differences in pharmacokinetics are linked to pharmacodynamic differences, alterations in therapeutic effect can result. Additionally, drug interactions are discussed in which 1 isomer is affected to a greater extent than the other, potentially causing not only an increase or decrease in effect, but also a change in pharmacologic action. Examples also are presented of the marketing of single isomer entities, with a discussion of the use of these products. Finally, preliminary policies of the Food and Drug Administration are discussed, as well as the potential implications of these policies. Conclusions: Drugs that are administered as stereoisomers can differ with respect to both pharmacokinetics and pharmacodynamics, and these differences may have profound implications in pharmacotherapy. All future investigations of drugs that exist as stereoisomers must take into account the pharmacokinetics and pharmacodynamics of both isomers to understand fully the observed phenomena.