THE PHARMACOKINETICS OF 1954U89, HYLPROPYL)-8-METHYL-7H-PYRROLO-(3,2-F)QUINAZOLINE, IN DOGS AND RATS AFTER INTRAVENOUS AND ORAL-ADMINISTRATION

1954U89, hylpropyl)-s-methyl-7H-pyrrolo-(3,2-f)quinazoline, is a poten t, lipid-soluble inhibitor of dihydrofolate reductase. The pharmacokin etics and bioavailability of 1954U89 were examined in male beagle dogs and male CD rats. Dogs received single intravenous (2.5 mg kg(-1)) an d oral (5.0 mg kg(-1)) doses of 1954U89 with and without successive ad ministration of calcium leucovorin. Single intravenous (5.0 mg kg(-1)) and oral (10 mg kg(-1)) doses of [1,3-C-14(2)]1954U89 were administer ed to rats. Plasma concentrations of total radiocarbon were determined by scintillation counting, and intact 1954U89 was measured by HPLC. T he mean plasma half-life was 3.2 +/- 0.62 and 4.2 +/- 0.68 h after int ravenous and oral administration, respectively, to dogs. The pooled pl asma half-life after intravenous administration to rats averaged 1 2 h ; a reliable plasma half-life value after oral administration could no t 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, respec tively, to dogs, and averaged 12 and 77 L h(-1) kg(-1) after intraveno us and oral administration, respectively, to rats. Neither clearance n or bioavailability of 1954U89 in dogs was affected significantly by ad ministration of calcium leucovorin. Absolute bioavailability was 54 +/ - 12% in dogs and 16% in rats. (C) 1997 by John Wiley & Sons, Ltd.