title: The pharmacokinetics of 1954U89, 1,3-diamino-7-(1-ethylpropyl)-8-methyl-7H-pyrrolo-(3,2-f)quinazoline, in dogs and rats after intravenous and oral administration.
abstract: 1954U89, 1,3-diamino-7-(1-ethylpropyl)-8-methyl-7H-pyrrolo-(3, 2-f)quinazoline, is a potent, lipid-soluble inhibitor of dihydrofolate reductase. The pharmacokinetics and bioavailability of 1954U89 were examined in male beagle dogs and male CD rats. Dogs received single intravenous (2.5 mg kg-1) and oral (5.0 mg kg-1) doses of 1954U89 with and without successive administration of calcium leucovorin. Single intravenous (5.0 mg kg-1) and oral (10 mg kg-1) doses of [1,3-14C2]1954U89 were administered to rats. Plasma concentrations of total radiocarbon were determined by scintillation counting, and intact 1954U89 was measured by HPLC. The mean plasma half-life was 3.2 +/- 0.62 and 4.2 +/- 0.68 h after intravenous and oral administration, respectively, to dogs. The pooled plasma half-life after intravenous administration to rats averaged 1.2 h; a reliable plasma half-life value after oral administration could not be determined. Mean total-body clearance was 2.4 +/- 0.39 and 4.5 +/- 1.1 L h-1 kg-1 after intravenous and oral administration, respectively, to dogs, and averaged 12 and 77 L h-1 kg-1 after intravenous and oral administration, respectively, to rats. Neither clearance nor bioavailability of 1954U89 in dogs was affected significantly by administration of calcium leucovorin. Absolute bioavailability was 54 +/- 12% in dogs and 16% in rats.
authors.affiliation: Division of Pharmacokinetics and Drug Metabolism, Wellcome Research Laboratories, Research Triangle Park, NC, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Studenberg
authors.forename: J L
authors.initials: JL
authors.lastname: Woolley
authors.forename: D V
authors.initials: DV
authors.lastname: Deangelis
authors.forename: W A
authors.initials: WA
authors.lastname: Wargin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000494:pharmacology; D008297:Male; D011758:Pyrroles / Q000032:analysis / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000032:analysis / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
chemical_list: C107680:1954U89; D000931:Antidotes; D005493:Folic Acid Antagonists; D011758:Pyrroles; D011799:Quinazolines; D002955:Leucovorin