PHARMACOKINETIC AND PHARMACODYNAMIC PROFILE OF TRIETHYLENE GLYCOL INDOMETHACIN ESTER AS A NEW ORAL PRODRUG

The pharmacokinetic and pharmacodynamic profile of triethylene glycol indomethacin ester (TIE), an indomethacin oral prodrug, was investigat ed after oral administration to rats (indomethacin 5 mg/kg; TIE 20 mg/ kg). In vitro enzymatic hydrolysis studies using rat plasma showed tha t TIE was quantitatively reconverted into indomethacin at a very fast rate. After TIE oral dosing, indomethacin mean peak plasma concentrati on was lower than after indomethacin administration (16.30 and 30.25 m u g/ml, respectively) and mean time to the peak plasma concentration w as slightly higher than that observed after indomethacin (4 and 3 h, r espectively). TIE oral administration to rats gave lower but relativel y constant indomethacin plasma levels for the observation period (24 h ). The results from the biological response time course of carrageenan -induced paw edema after indomethacin and TIE administration showed th at both drug and prodrug were able to inhibit the inflammatory process over the observation period (7 h). Furthermore, the paw/blood concent ration ratio of indomethacin 3 h after carrageenan injection was simil ar after oral administration of indomethacin or TIE. TIE pharmacokinet ic profile could be attributed to a different absorption of the prodru g in the gastrointestinal tract compared to indomethacin.