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.

Metabolism, Pharmacokinetics, and Protein Covalent Binding of Radiolabeled Maxipost (Bms-204352) in Humans

“…Metabolism appeared to be predominant in the disposition of BMS-204352 in rats and dogs (Krishna et al, 2002d). Following an intraarterial infusion of [ 14 C]BMS-204352 to rats (6 mg/kg) and dogs (2 mg/kg), the AUC values of the unchanged BMS-204352 represented only a very small fraction of the plasma radioactivity.…”

“…Units for AUC: BMS-204352, ng ⅐ h/ml and radioactivity, ng-Eq ⅐ h/ml). b Portions of pharmacokinetics data in dogs and rats have been presented previously (Krishna et al, 2002d). …”

“…This compound has the potential to prevent and treat ischemic stroke. The fluoro-oxyindole, BMS-204352, provided significant levels of cortical neuroprotection in rat models of stroke by augmenting an endogenous mechanism for regulating Ca 2ϩ entry and membrane potential to protect the neurons (Cheney et al, 2001;Gribkoff et al, 2001).Metabolism appeared to be predominant in the disposition of BMS-204352 in rats and dogs (Krishna et al, 2002d). Following an intraarterial infusion of [ 14 C]BMS-204352 to rats (6 mg/kg) and dogs (2 mg/kg), the AUC values of the unchanged BMS-204352 represented only a very small fraction of the plasma radioactivity.…”

AMIDE N-GLUCURONIDATION OF MAXIPOST CATALYZED BY UDP-GLUCURONOSYLTRANSFERASE 2B7 IN HUMANS

“…The compound had a brain/plasma exposure ratio of 9:1 following an intravenous bolus dose of 5 mg/kg in rats . MaxiPost showed extensive metabolism in rats and dogs (Krishna et al, 2002) and exhibited protein covalent binding in plasma of rats dosed with the 14 C-labeled drug (Zhang et al, 2003a).…”

Protein Covalent Binding of Maxipost Through a Cytochrome P450-Mediated Ortho-Quinone Methide Intermediate in Rats

“…BMS-204352 was 99.5% protein bound in rat serum (Krishna et al, 2001). Following an intraarterial infusion or oral dose of [ 14 C]BMS-204352 (6 mg/kg) (Krishna et al, 2002), the elimination of total radioactivity in plasma was very slow compared with that of the parent compound. Radioactivity was primarily excreted in the feces (more than 85% of administered dose over a 7-day collection period).…”