Absorption and metabolism of anitrazafen, a topically effective anti-inflammatory agent, in the rat

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Abstract
The metabolism and pharmacokinetics of anitrazafen, a topically effective antiinflammatory agent [a prostaglandin E2 and thromboxane B2 synthesis inhibitor], were investigated in the rat after oral, s.c. and topical administration. [14C]Anitrazafen is rapidly absorbed from the gastrointestinal tract and subsequent metabolism is rapid and extensive; biliary excretion is the major route of elimination. After s.c. or topical administration, elimination of [14C]anitrazafen was delayed due to a slower rate of systemic absorption. Pharmacokinetic studies confirmed these results. After oral administration peak concentration of the parent drug were attained within 1 h; plasma concentration of 14C was an order of magnitude greater than those of the unchanged drug. The apparent volume of distribution of anitrazafen was high (1121/kg) consistent with observed tissue 14C concentrations. S.c. administration resulted in delayed absorption but with maximum bioavailability of the parent drug. Absorption was slowest following topical application. Anitrazafen was extensively metabolized in rats. No unchanged drug was found in excreta. The most important mechanism of biotransformation was oxidative O-demethylation, with glucuronide or sulfate conjugates of 2 isomeric mono-O-demethylated and the di-O-demethylated analogs of anitrazafen as metabolites.

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