Abstract
LY288513 [(4S,5R)-trans-N-(4-bromophenyl)-3-oxo-4,5-diphenyl-1- pyrazolidinecarboxamide] has been developed as a cholecystokinin-B antagonist for anxiolytic indications. In the drug disposition studies reported herein, we found LY288513 was metabolized rapidly in mice and rats to form a glucuronide adduct. This metabolite was isolated from rodent urine and further characterized to determine whether a ring-nitrogen or the oxygen atom in the pyrazolidinone nucleus of LY288513 was bonded to the glucuronide. Using 13C NMR plus two-dimensional rotating frame Overhauser enhancement spectroscopy analysis and IR analysis of model compounds, we determined the metabolite was an O-glucuronide. The major elimination pathway for [14C]LY288513 was fecal, with > 75% of total radiocarbon excreted within 24 hr. Plasma levels for parent and metabolite in the three species varied substantially. The plasma half-life was significantly longer in dogs (approximately 12 hr) than mice (approximately 24 hr) or rats (2.6-3.6 hr). Consistent with this, in dogs relatively little O-glucuronide was observed in plasma, but in rats and mice the AUCs for glucuronide were greater than the parent AUC. A dose-ranging study in rats revealed oral absorption of LY288513 is nonsaturated, even after 800 mg/kg oral doses. A plot of AUC vs. dose revealed a consistent overproportional increase in AUC for both parent and glucuronide metabolite with increasing dose.
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|