title: Pharmacokinetics and dose proportionality of BMS-204352 after intravenous administration to dogs.
abstract: BMS-204352 is a novel maxi-K channel opener that is being developed for the treatment for stroke. The current study was designed to evaluate the dose proportionality and pharmacokinetics of BMS-204352 in dogs. In an open, three-way crossover study, three beagle dogs received a single intravenous dose of BMS-204352 as a 6-min infusion into the femoral vein at 0.4, 0.9, and 2.0 mg/kg dose levels. There was at least a 1-week washout period between treatments. Serial blood samples were collected for up to 32 h post dose and plasma samples were analyzed for the concentrations of intact BMS-204352 using a validated liquid chromatographic mass spectrometric (LC/MS) method. Pharmacokinetic analysis was performed using a non-compartmental method. Results indicated that peak BMS-204352 concentrations (C(max)) and area under the plasma concentration-time curves (AUC) values increased in a dose proportional manner. Mean residence time (MRT, 18.2-21.9 h) and elimination half-life (T(half), 13.5-17 h) did not change with dose. There was no dose dependency in the mean BMS-204352 total body clearance (CLT, 134-158 ml/h/kg) and mean steady state volume of distribution (VSS, 2839-3291 ml/kg). The high VSS value indicated that BMS-204352 was distributed extensively in the extravascular tissues. In conclusion, BMS-204352 exhibits linear pharmacokinetics over the dose range tested (0.4-2 mg/kg).
authors.affiliation: Clinical Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. rajesh.krishna@bms.com
authors.forename: Rajesh
authors.initials: R
authors.lastname: Krishna
authors.forename: Vinod R
authors.initials: VR
authors.lastname: Shah
authors.forename: Subbaro
authors.initials: S
authors.lastname: Mantha
authors.forename: Nimish N
authors.initials: NN
authors.lastname: Vachharajani
authors.forename: Nuggehally
authors.initials: N
authors.lastname: Srinivas
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D015221:Potassium Channels / Q000819:agonists
chemical_list: C424388:BMS204352; D007211:Indoles; D018696:Neuroprotective Agents; D015221:Potassium Channels