Pharmacokinetic Analysis of the Enantiomeric Inversion of Chiral Nonsteroidal Antiinflammatory Drugs

Equations describing plasma concentration–time courses of the individual enantiomers of chiral 2-arylpropionic acid nonsteroidal antiinflammatory drugs were derived from a general model. The model assumes first-order absorption and elimination of the enantiomers with presystemic and/or systemic R-to-S enantiomeric inversion. Utilizing reported pharmacokinetic parameters, plasma concentrations of the enantiomers of ibuprofen (IB) were simulated. In the case of presystemic inversion, S:R plasma concentration ratios remained constant after an initial rise; the ratio progressively increased with time, however, when systemic inversion was assumed. Under the assumption of simultaneous systemic and presystemic inversion, the increase in the ratio in the postabsorptive phase was preceded by a steeper increase during absorption. Furthermore, it was shown that purturbation of IB absorption from the gastrointestinal tract may serve as an important discriminative measure for identification of the inversion site. For systemic and presystemic inversions, negative and positive sigmoidal relationships, respectively, were observed between the S:R concentration ratio 5 hr after drug administration and the time to reach the maximum plasma concentration. The applicability of the model to previously reported IB data is discussed.