title: Characterization of an O-glucuronide metabolite of the CCK-B antagonist LY288513 and its plasma levels in mouse, rat, and dog.
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.
authors.affiliation: Department of Drug Metabolism, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Woodland
authors.forename: W J
authors.initials: WJ
authors.lastname: Ehlhardt
mesh_terms: D000818:Animals; D001711:Biotransformation; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D005965:Glucuronates / Q000097:blood; D006727:Hormone Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet
chemical_list: D005965:Glucuronates; D006727:Hormone Antagonists; D011720:Pyrazoles; C074681:1-(4-bromophenylaminocarbonyl)-4,5-diphenyl-3-pyrazolidinone; D002766:Cholecystokinin