TAURINE CONJUGATION OF IBUPROFEN IN HUMANS AND IN RAT-LIVER IN-VITRO - RELATIONSHIP TO METABOLIC CHIRAL INVERSION

Following administration of a single oral dose (400 mg) of RS-ibuprofe n (RS-IBP) to humans, a novel metabolite was isolated from urine and i dentified by tandem mass spectrometry as the taurine conjugate of IBP (IBP-Tau). The corresponding glycine conjugate was sought but was not detected in these studies. Quantitative analyses indicated that taurin e conjugation represents a minor biotransformation pathway for IBP (1. 52 +/- 0.43% of the dose over 24 h, n = 4), but it is nonetheless one of mechanistic significance in that it requires the prior formation of the coenzyme A thioester of IBP (IBP-CoA). The latter conjugate, whic h has not been detected in vivo because of its intracellular compartme ntalization, plays a key role in the metabolic chiral inversion of R- to S-IBP. By means of stereoselective gas chromatography-mass spectrom etry, it was found that IBP liberated from the urinary IBP-Tau under n onracemizing conditions consisted mainly (ca. 87%) of molecules of S c onfiguration. From separate experiments with volunteers given a pseudo racemic mixture of the drug (R-IBP/S-[H-2(3)]IBP), it was shown that t he majority of the S-IBP-Tau was derived from S-IBP1 rather than from R-IBP by way of chiral inversion. These findings, together with the re sults of in vitro experiments with rat liver mitochondrial preparation s and isolated rat hepatocytes, demonstrate that although activation o f IBP to its CoA thioester favors the R enantiomer over its antipode, S-IBP also participates in CoA-dependent reactions, including metaboli c chiral inversion.