PHARMACOKINETICS OF INDOMETHACIN OCTYL ESTER (PRODRUG) AND INDOMETHACIN PRODUCED FROM THE PRODRUG

A prodrug of indomethacin, indomethacin octyl ester (IM-OE), was synth esized and its pharmacokinetics was investigated in rat. To describe t he time course of the plasma indomethacin and IM-OE after intravenous (iv) and oral administrations, a pharmacokinetic model with four compa rtments was developed. Indomethacin rapidly appeared in plasma after i v administration of IM-OE and declined in a monoexponential manner, wi th a rapid decline and low plasma levels of IM-OE. The plasma concentr ations of indomethacin after oral administration of IM-OE were much lo wer than those after oral administration of indomethacin. The high con centrations of IM-OE compared with indomethacin were detected in liver 3 h after oral dosing of the prodrug, although IM-OE was not detected in plasma. A good fit was obtained between the observed and calculate d curves based on the model, which includes a conversion rate constant of IM-OE to indomethacin for both iv and oral dosings of IM-OE. Addit ionally, the model could successfully describe the plasma concentratio n versus time profiles after indomethacin dosings.