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. © 1997 John Wiley & Sons, Ltd.