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Vol. 29, Issue 12, 1608-1613, December 2001
Identification of Urinary Mercapturic Acid Derivatives
in Rats and Humans
Departments of Drug Metabolism (G.K.P., Q.C., Y.T., J.S.N., M.P.B.,
G.A.D., C.F., R.A.S., D.C.E., T.A.B., W.T.), and Chemistry (P.R.G.),
Merck Research Laboratories, Rahway, New Jersey
The metabolism of diclofenac has been reported to produce reactive
benzoquinone imine intermediates. We describe the identification of
mercapturic acid derivatives of diclofenac in rats and humans. Three
male Sprague-Dawley rats were administered diclofenac in aqueous
solution (pH 7) at 50 mg/kg by intraperitoneal injection, and urine was
collected for 24 h. Human urine specimens were obtained, and
samples were pooled from 50 individuals. Urine samples were analyzed by
liquid chromatography-tandem mass spectrometry (LC/MS/MS). Two
metabolites with MH+ ions at
m/z 473 were detected in rat urine and
identified tentatively as N-acetylcysteine conjugates of
monohydroxydiclofenac. Based upon collision-induced fragmentation of
the MH+ ions, accurate mass measurements of product
ions, and comparison of LC/MS/MS properties of the metabolites with
those of synthetic reference compounds, one metabolite was assigned as
5-hydroxy-4-(N-acetylcystein-S-yl)diclofenac and the other as
4'-hydroxy-3'-(N-acetylcystein-S-yl)diclofenac. The former conjugate also was detected in the pooled human urine sample
by multiple reaction-monitoring LC/MS/MS analysis. It is likely that
these mercapturic acid derivatives represent degradation products of
the corresponding glutathione adducts derived from diclofenac-2,5-quinone imine and 1',4'-quinone imine, respectively. Our
data are consistent with previous findings, which suggest that
oxidative bioactivation of diclofenac in humans proceeds via
benzoquinone imine intermediates.
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