The metabolism and kinetics of tiflorex in the rat.

14C-Tiflorex given either orally or intravenously to male rats (10 mg/kg; 250 microCi) was well absorbed orally; greater than 70% of the dose was excreted in the urine in the first 48 hr after dosing by either route of administration. Inasmuch as part of the dose (10%) was excreted in the feces after iv administration, it is probable that biliary excretion is a route of elimination. This was shown to be so by cannulation of the bile duct. The major route of metabolism was S-oxidation to give the sulfoxides and sulfones of tiflorex (7% each) and nortiflorex (10 and 20%, respectively) which were excreted together with the unchanged drug (1%) in the 0- to 48-hr urine. Examination of the plasma for the unchanged drug and its metabolites showed the drug to be rapidly absorbed orally, maximum levels being attained within 30 min. The plasma half-life for the elimination phase of the unchanged drug was relatively long (7.5 hr) compared with the metabolites (2.5 hr) with the exception of nortiflorex sulfone (9.8 hr) and two as yet unidentified metabolites which had half-lives in excess of 24 hr. The latter three compounds were responsible for the relatively long plasma half-life of total radioactivity (ca. 13 hr). The ratio of the areas under the plasma curve for unchanged drug indicated a low bioavailability (30%). It appears that the predominant route of metabolism of this group of compounds in the rat, p-hydroxyltation had been blocked by the trifluoromethylthio group, with consequent emphasis on S-oxidation.