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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
Author(s) -
STUDENBERG S. D.,
WOOLLEY J. L.,
DEANGELIS D. V.,
WARGIN W. A.
Publication year - 1997
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/(sici)1099-081x(199707)18:5<433::aid-bdd32>3.0.co;2-p
Subject(s) - bioavailability , beagle , pharmacokinetics , oral administration , pharmacology , chemistry , half life , medicine
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‐ 14 C 2 ]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.