title: Metabolism and disposition of the antifolate LY231514 in mice and dogs.
abstract: The metabolism and disposition of LY231514 was studied in mice and dogs. LY231514 is a novel pyrrotopyrimidine-based multi-target antifolate (MTA) showing broad in vivo antitumor activity in mouse models and is currently in phase II human clinical trials. Doses (iv) of the compound showed high plasma levels, resulting in AUC values of 30-33 micrograms-hr/ml for mice and dogs after 20 and 7.5 mg/kg doses, respectively. The compound was eliminated rapidly. Half-life values for mice and dogs were about 7 and 2 hr, respectively. In vitro plasma binding measured 56% in mice, 46% in dogs, and 81% in humans. Fecal elimination was the major excretion pathway in mice after single iv doses of [14C]LY231514. Urine constituted the major route of excretion in dogs. Parent LY231514 accounted for the majority of urinary radiocarbon in mice (90%) and dogs (68%). Minor metabolites were found in urine, but the amounts were too small to isolate or identify. Based on an earlier observation that LY231514 photodegraded to produce reaction products having similar retention times as these minor urinary isolates, a photo-oxidation system was developed which in fact produced these metabolites. Subsequently, these photolytically-produced materials were used as standards to identify two novel in vivo metabolites formed by oxidation of the pyrrolo-pyrimidine ring system of LY231514. The oxidative transformations are similar to those observed for tryptophan and other indoles in that the pyrrole ring is oxidized to give an amide; further oxidation cleaves this ring, one ring carbon is lost, and a ketone is formed.
authors.affiliation: Department of Drug Metabolism, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Woodland
authors.forename: C J
authors.initials: CJ
authors.lastname: Barnett
authors.forename: D E
authors.initials: DE
authors.lastname: Dorman
authors.forename: J M
authors.initials: JM
authors.lastname: Gruber
authors.forename: C
authors.initials: C
authors.lastname: Shih
authors.forename: L A
authors.initials: LA
authors.lastname: Spangle
authors.forename: T M
authors.initials: TM
authors.lastname: Wilson
authors.forename: W J
authors.initials: WJ
authors.lastname: Ehlhardt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004285:Dogs; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics*; D005971:Glutamates / Q000493:pharmacokinetics*; D006147:Guanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006207:Half-Life; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D000068437:Pemetrexed; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase