Metabolic Disposition of 14C‐Bromfenac in Healthy Male Volunteers

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Abstract
The metabolic disposition of 14C‐bromfenac, an orally active, potent, nonsteroidal, nonnarcotic, analgesic agent was investigated in six healthy male subjects after a single oral 50‐mg dose. The absorption of radioactivity was rapid, producing a mean maximum plasma concentration (Cmax) of 4.9 ± 1.8 μgṁequiv/mL, which was reached 1.0 ± 0.5 hours after administration. Unchanged drug was the major component found in plasma, and no major metabolites were detected in the plasma. Total radioactivity recovered over a 4‐day period from four of the six subjects averaged 82.5% and 13.2% of the dose in the urine and feces, respectively. Excretion into urine was rapid; most of the radioactivity was excreted during the first 8 hours. Five radioactive chromatographic peaks, a cyclic amide and four polar metabolites, were detected in 0‐ to 24‐hour urine samples. Similarity of metabolite profiles between humans and cynomolgus monkeys permitted use of this animal model to generate samples after a high dose for structure elucidation. Liquid chromatography/mass spectrometry (LC/MS) analysis of monkey urine samples indicated that the four polar metabolites were two pairs of diastereoisomeric glucuronides whose molecular weight differed by two daltons. Enzyme hydrolysis, cochromatography, and LC/MS experiments resulted in the identification of a hydroxylated cyclic amide as one of the aglycones, which formed a pair of diastereoisomeric glucuronides after conjugation. Data also suggested that a dihydroxycyclic amide formed by the reduction of the ketone group that joins the phenyl rings formed the second pair of diastereoisomeric glucuronides. Further, incubation of various reference standards in control (blank) urine and buffer with and without creatinine indicated that the hydroxy cyclic amide released from enzyme hydrolysis can undergo ex vivo transformations to a condensation product between creatinine and an α‐keto acid derivative of the hydroxy cyclic amide that is formed by oxidation and ring opening. Further experiments with a dihydroxylated cyclic amide after reduction of the keto function indicated that it too can form a creatinine conjugate.