The biotransformation of fluproquazone in man and several animal species

The biotransformation of 4-(p-fluorophenyl)-1-isopropyl-7-methyl-2(1H)-quinazolinone (fluproquazone) has been investigated in man, mouse, rat, rabbit, and dog. Single oral doses of 3H-fluproquazone were administered to the animals (15 mg/kg). Human volunteers received 100 mg 3H-fluproquazone t.i.d. for 5 days (3.8 mg/kg). Two potential metabolites were synthesized: 4-(p-fluorophenyl)-1,2-dihydro-1-isopropyl-2-oxo-7-quinazolinecarboxylic acid (4) and 4-(p-fluorophenyl)-7-hydroxymethyl-1-isopropyl-2(1H)-quinazolinone (11). The human urinary metabolites of fluproquazone were separated and purified by a combination of extractions and liquid chromatography on reversed-phase columns, and structures were proposed on the basis of identify with known standards, mass spectral data, and retention time comparison. Definitive structures were assigned to five metabolites. Fluproquazone and its metabolites were characterized and quantitated in the blood, urine, and feces of man, mouse, rat, rabbit, and dog by high-pressure liquid chromatography coupled to a radioactivity monitor or by reverse isotope dilution analysis. Significant quantities of fluproquazone were noted in the blood of all species. The major circulating metabolite in blood at or near the peak of radioactivity was 11 in rat, mouse, and dog and 4 in man and rabbit. In all species analyzed, 4 was the major metabolite excreted in the urine and feces. In man the minor metabolites consisted of 11 as a conjugate and several phenolic derivatives also conjugated. The animals were exposed to the same major metabolite as man and each minor metabolite found in man, with the exception of a few very minor ones, was identified in at least one of the animal species. The metabolite pattern did not vary significantly among the 3 human subjects analyzed nor over the 5-day dosing period. Two biotransformation pathways were identified. The major pathway was sequential oxidation with or without conjugation of the 7-methyl group; aromatic hydroxylation and conjugation was a minor pathway.