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MA Shirley, X Guan, DG Kaiser, GW Halstead and TA Baillie
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle.
Following administration of a single oral dose (400 mg) or RS-ibuprofen (RS-IBP) to humans, a novel metabolite was isolated from urine and identified 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 taurine 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, which has not been detected in vivo because of its intracellular compartmentalization, plays a key role in the metabolic chiral inversion of R- to S-IBP. By means of stereoselective gas chromatography-mass spectrometry, it was found that IBP liberated from the urinary IBP-Tau under nonracemizing conditions consisted mainly (ca. 87%) of molecules of S configuration. From separate experiments with volunteers given a pseudoracemic mixture of the drug (R-IBP/S- [2H3]IBP), it was shown that the majority of the S-IBP-Tau was derived from S-IBP, rather than from R-IBP by way of chiral inversion. These findings, together with the results of in vitro experiments with rat liver mitochondrial preparations and isolated rat hepatocytes, demonstrate that although activation of IBP to its CoA thioester favors the R enantiomer over its antipode, S-IBP also participates in CoA- dependent reactions, including metabolic chiral inversion.
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