title: Metabolism, pharmacokinetics, and protein covalent binding of radiolabeled MaxiPost (BMS-204352) in humans.
abstract: 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 (14)C-labeled MaxiPost in healthy male volunteers as well as in dogs and rats. After each human subject received a single dose of 10 mg (14)C-labeled BMS-204352 (50 microCi) 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 (14)C-labeled BMS-204352 were observed in humans, dogs, and rats.
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Route 206 and Province Line Road, Princeton, NJ 08543-4000, USA. donglu.zhang@bms.com
authors.forename: Donglu
authors.initials: D
authors.lastname: Zhang
authors.forename: Rajesh
authors.initials: R
authors.lastname: Krishna
authors.forename: Lifei
authors.initials: L
authors.lastname: Wang
authors.forename: Jianing
authors.initials: J
authors.lastname: Zeng
authors.forename: James
authors.initials: J
authors.lastname: Mitroka
authors.forename: Renke
authors.initials: R
authors.lastname: Dai
authors.forename: Narayanan
authors.initials: N
authors.lastname: Narasimhan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Reeves
authors.forename: Nuggehally R
authors.initials: NR
authors.lastname: Srinivas
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Klunk
mesh_terms: D000328:Adult; D000818:Animals; D001798:Blood Proteins / Q000032:analysis / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000032:analysis / Q000378:metabolism; D004285:Dogs; D006801:Humans; D007211:Indoles / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats
chemical_list: C424388:BMS204352; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D007211:Indoles