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METABOLISM, PHARMACOKINETICS, AND PROTEIN COVALENT BINDING OF RADIOLABELED MAXIPOST (BMS-204352) IN HUMANS

Departments of Pharmaceutical Candidate Optimization (D.Z., L.W., J.Z., J.M., R.D., N.N., L.J.K.) and Clinical Discovery (R.K., R.A.R., N.R.S.), Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey

MaxiPost [(3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one); BMS-204352] is an investigational maxi-K channel opener to treat ischemic stroke. This study reports the disposition, metabolism, pharmacokinetics, and protein covalent binding of ¹⁴C-labeled MaxiPost in healthy male volunteers as well as in dogs and rats. After each human subject received a single dose of 10 mg ¹⁴C-labeled BMS-204352 (50 µCi) as a 5-ml intravenous infusion lasting 5 min, the plasma radioactivity concentrations showed a unique profile, wherein the concentration appeared to increase initially, followed by a terminal decline. The mean terminal t_1/2 of plasma radioactivity (259 h) was prolonged compared with that of unchanged parent (37 h). Furthermore, the extractability of radioactivity in plasma decreased over time, reaching approximately 20% at 4 h after dosing. The unextractable radioactivity was covalently bound to plasma proteins through a des-fluoro-des-methyl BMS-204352 lysine adduct. Unchanged BMS-204352 and minor metabolites were identified in plasma extract following protein precipitation. The recovery of the radioactive dose in urine and feces was nearly complete in 14-day collections (approximately 37% in urine and 60% in feces). The N-glucuronide of the parent was the prominent metabolite in urine (16.5% of dose), whereas the parent was a major drug-related component in feces (11% of dose). Similar disposition, metabolism, pharmacokinetic, and protein covalent binding properties of ¹⁴C-labeled BMS-204352 were observed in humans, dogs, and rats.