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

Abstract

1. The metabolism and pharmacokinetics of anitrazafen, a topically effective anti-inflammatory agent, have been investigated in the rat after oral, subcutaneous and topical administration.

2. [¹⁴C] Anitrazafen is rapidly absorbed from the gastro-intestinal tract and subsequent metabolism is rapid and extensive; biliary excretion is the major route of elimination. After subcutaneous or topical administration, elimination of [¹⁴C] anitrazafen was delayed due to a slower rate of systemic absorption.

3. Pharmacokinetic studies confirmed these results. After oral administration peak concn. of parent drug were attained within 1 h; plasma concn. of ¹⁴C were an order of magnitude greater than those of unchanged drug. The apparent volume of distribution of anitrazafen was high (1121/kg) consistent with observed tissue ¹⁴C concentrations. Subcutaneous administration resulted in delayed absorption but with maximum bioavail-ability of parent drug. Absorption was slowest following topical application.

4. 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 sulphate conjugates of two isomeric mono-O-demethylated and the di-O-demethylated analogues of anitrazafen, as metabolites.