Abstract

In contrast to earlier reports, indomethacin-¹⁴C has been found to undergo extensive O-demethylation and N-deacylation in man. Isotope dilution analyses for unchanged indomethacin, its desmethyl, desbenzoyl and desmethyl-desbenzoyl metabolites and their respective conjugates revealed that unchanged drug (free plus conjugated forms) constituted the major species present only in the earliest plasma and urine samples. The respective time courses of appearances in plasma and of urinary excretion of indomethacin and its metabolites suggest that demethylatien followed by deacylation constitutes the major pathway for catabolism in man and direct deacylation a miner one. Fecal excretion of radioactivity was variable ranging from 21 to 42% of the dose through four days but was invariably comprised predominantly of the two demethylated metabolites (>90%), almost entirely in their unconjugated forms. Material balance considerations and absorption kinetics preclude reabsorption of significant levels of unchanged indomethacin, suggesting a virtual absence of enterohepatic recycling in man. Kinetic analysis is consistent with the concept of at least two nonsampleable tissue pools for indomethacin and its conjugate(s) ; one with a half-life equal to that for the plasma pool, and a second of considerably longer half-life, providing a reservoir for regeneration of free indomethacin. The present findings indicate that the results of earlier clinical studies based upon nonspecific isotope or fluorescence methodology are subject to considerable reinterpretation.