Enantioselective assays in comparative bioavailability studies of racemic drug formulations: nice to know or need to know?

The importance of enantiospecific assays in studying pharmacokinetic/pharmacodynamic (PK/PD) and drug-drug interactions of racemic drugs is widely recognized. Use of such assays in comparative bioavailability studies, however, remains controversial. This commentary proposes a PK/PD-based rationale for deciding whether an enantioselective assay is important in such studies. Racemic drugs are divided into three major categories: those with negligible or nonenantioselective first-pass metabolism (category I), those where the first-pass metabolism of the less-active enantiomer is predominant (category II), and those where the first-pass metabolism of the more active and/or toxic enantiomer is predominant (category III). In addressing the need for assay selectivity, a simple analogy is made between these drug categories and the protein-binding phenomenon. Enantioselective assays are not essential for category I drugs, or for category II drugs in the majority of cases. A special consideration, however, is needed for those category II drugs that undergo racemic inversion that may be influenced by the dose level and/or the residence time of the drug formulation in the gastrointestinal tract. It is with category III drugs that enantioselective assays become important, especially when metabolism, distribution, and/or elimination processes of the active or toxic enantiomer are saturable, leading to variable enantiomeric ratios in the plasma. Factors contributing to these ratio changes include routes of administration, dose level, and input rate differences. In put rate differences are particularly relevant to bioavailability evaluation of category III drugs.