RT Journal Article
SR Electronic
T1 METABOLISM, PHARMACOKINETICS, AND PROTEIN COVALENT BINDING OF RADIOLABELED MAXIPOST (BMS-204352) IN HUMANS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 83
OP 93
DO 10.1124/dmd.104.001412
VO 33
IS 1
A1 Donglu Zhang
A1 Rajesh Krishna
A1 Lifei Wang
A1 Jianing Zeng
A1 James Mitroka
A1 Renke Dai
A1 Narayanan Narasimhan
A1 Richard A. Reeves
A1 Nuggehally R. Srinivas
A1 Lewis J. Klunk
YR 2005
UL http://dmd.aspetjournals.org/content/33/1/83.abstract
AB 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 t1/2 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. The American Society for Pharmacology and Experimental Therapeutics