title: Disposition of radiolabeled BMS-204352 in rats and dogs.
abstract: BMS-204352, a maxi-K channel opener, is currently under development for the treatment of stroke. The objective of this study was to determine the pharmacokinetics, mass balance and absolute oral bioavailability of [(14)C]-BMS-204352 in rats and dogs. [(14)C]-BMS-204352 was administered, to rats (n=10/group; parallel design, 6 mg/kg) and dogs (n=4/group; crossover design, 2 mg/kg), as an oral (PO) or as a 3-min intraarterial (IA) infusion in rats and a 6-min intravenous (i.v.) infusion in dogs. Blood, urine, and feces samples were collected and analyzed for unchanged BMS-204352 (plasma) using a validated LC/MS assay and for total radioactivity (plasma, urine, feces) using liquid scintillation counting. The mean total body clearance (CLT) and steady-state volume of distribution (VSS) values for the unchanged BMS-204352 were 2.58 +/- 0.48 l/h/kg and 6.3 +/- 1.14 l/kg, respectively, in rats and 0.21 +/- 0.02 l/h/kg and 4.06 +/- 0.47 l/kg, respectively, in dogs. In both species, the elimination half-life of total radioactivity was significantly longer as compared to the unchanged drug. After IA administration of radiolabeled BMS-204352 to rats, ca. 5.9 and 85% of radioactivity was recovered within 7 days in urine and feces, respectively; corresponding recoveries after PO dosing were 4.5 and 99.5%, respectively. The recoveries were similar in dogs, i.e., ca. 5.2 and 83% of administered radioactivity recovered in urine and feces, respectively, for IV dose and ca. 4 and 86%, respectively, for PO dose. These data indicate that nonrenal (biliary) elimination in both species was predominant. Based on comparable urinary recovery of radioactivity and plasma AUCs of radioactivity, the extent of oral absorption of BMS-204352 appeared to be complete in both species. The absolute oral bioavailability was 55% in rats and 79% in dogs. Bioavailability and extent of absorption data suggest evidence of first pass metabolism of BMS-204352 in the rat and dog.
authors.affiliation: Clinical Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08540, USA. rajesh.krishna@bms.com
authors.forename: Rajesh
authors.initials: R
authors.lastname: Krishna
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.forename: Nuggehally R
authors.initials: NR
authors.lastname: Srinivas
authors.forename: Vinod
authors.initials: V
authors.lastname: Shah
authors.forename: Janice M
authors.initials: JM
authors.lastname: Pursley
authors.forename: Mark
authors.initials: M
authors.lastname: Arnold
authors.forename: Nimish N
authors.initials: NN
authors.lastname: Vachharajani
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002250:Carbon Radioisotopes; D004285:Dogs; D007211:Indoles / Q000493:pharmacokinetics*; D008297:Male; D018696:Neuroprotective Agents / Q000493:pharmacokinetics*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy*
chemical_list: C424388:BMS204352; D002250:Carbon Radioisotopes; D007211:Indoles; D018696:Neuroprotective Agents; D015221:Potassium Channels