Pharmacokinetics of Tiaprofenic Acid in Humans: Lack of Stereoselectivity in Plasma Using Both Direct and Precolumn Derivatization Methods

Abstract

A new direct stereospecific HPLC method was developed to assay tiaprofenic acid (TA) enantiomers in plasma. It has been reported previously that TA exhibits nonstereoselective pharmacokinetics in humans using an indirect stereospecific HPLC assay. The indirect assay involves formation of diastereomers through reaction of the carboxylic acid moiety with a coupling reagent, 2,2,2-trichloroethyl chloroformate, to form a mixed anhydride, followed by formation of an amide using l-leucinamide. A recent report suggests the possibility of the existence of a small but significant difference between the pharmacokinetics of TA enantiomers in humans when a direct HPLC method was used for analysis of plasma samples. The discrepancy between the two reports may be explained by partial or complete chiral conversion during derivatization. We have studied the possibility of racemization using both direct and indirect methods. In addition, the pharmacokinetics of TA enantiomers were compared after single oral doses of 300mg of TA administered to 4 healthy volunteers as a conventional tablet and a sustained release formulation using both assays. The reported direct HPLC assay is suitable for analysis of plasma samples as reflected from small intra- and interday coefficients of variation (<10%) and suitable sensitivity (0.025 µg/mL). There was no chiral conversion when a stereochemically pure (>98.6%) enantiomer was subjected to the direct method. The derivatization of the enantiomers with l-leucinamide, however, resulted in approximately 7% chiral conversion. Nevertheless, the plasma concentration–time profiles of (R)- and (S)-TA were not significantly different using either methods. This finding indicates that both direct and indirect HPLC methods are suitable for pharmacokinetic study of TA enantiomers. There is no evidence for the existence of stereoselectivity in the disposition kinetics of TA enantiomers in humans.