Received for publication July 9, 2004.
Revised October 19, 2004.
Accepted for publication October 19, 2004.

METABOLISM, PHARMACOKINETICS, AND PROTEIN COVALENT BINDING OF RADIOLABELED MAXIPOST IN HUMANS

Abstract

MaxiPost (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 C-14 labeled MaxiPost in healthy male volunteers as well as in dogs and rats. After each human subject received a single dose of 10 mg C-14 labeled BMS-204352 (50 micro Ci) as a 5-mL intravenous infusion lasting 5 minutes, the plasma radioactivity concentrations showed a unique profile, wherein the concentration appeared to increase initially followed by a terminal decline. The mean terminal T-half of plasma radioactivity (259 hours) was prolonged compared to that of unchanged parent (37 hours). Further, the extractability of radioactivity in plasma decreased over time reaching approximately 20% at 4 hour 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 the feces (11% of dose). Similar disposition, metabolism, pharmacokinetic, and protein covalent binding properties of C-14 labeled BMS-204352 were observed in humans, dogs, and rats.

Key words: bioactivation, covalent drug binding, drug disposition, drug toxicity, pharmacokinetics