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 investigated after oral administration to rats (indomethacin 5 mg/kg; TIE 20 mg/kg). In vitro enzymatic hydrolysis studies using rat plasma showed that TIE was quantitatively reconverted into indomethacin at a very fast rate. After TIE oral dosing, indomethacin mean peak plasma concentration was lower than after indomethacin administration (16.30 and 30.25 mu g/ml, respectively) and mean time to the peak plasma concentration was slightly higher than that observed after indomethacin (4 and 3 h, respectively). TIE oral administration to rats gave lower but relatively 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 that both drug and prodrug were able to inhibit the inflammatory process over the observation period (7 h). Furthermore, the paw/blood concentration ratio of indomethacin 3 h after carrageenan injection was similar after oral administration of indomethacin or TIE. TIE pharmacokinetic profile could be attributed to a different absorption of the prodrug in the gastrointestinal tract compared to indomethacin.