PROBENECID INHIBITS THE GLUCURONIDATION OF INDOMETHACIN AND O-DESMETHYLINDOMETHACIN IN HUMANS

Indomethacin is metabolized in humans by O-demethyiation, and by acyl glucuronidation to the 1-O-glucuronide, Indomethacin, its metabolite, and their conjugates can be measured directly by gradient high-pressur e liquid chromatographic analysis without enzymic deglucuronidation. T he pharmacokinetic profile of indomethacin and some preliminary pharma cokinetic parameters of indomethacin obtained from one human volunteer are given. In plasma only the parent drug indomethacin is present, wh ile in urine the acyl and ether glucuronides are present in high conce ntrations. This confirms other reports that indomethacin and O-desmeth ylindomethacin may be glucuronidated in the kidney. Probenecid is a kn own substrate for renal glucuronidation. If indomethacin is glucuronid ated in the Human kidney like probenecid, then this glucuronidation mi ght be reduced or inhibited under probenecid co-medication. This pilot experiment shows that probenecid reduced the acyl glucuronidation of indomethacin by 50% and completely inhibited the formation of O-desmet hylindomethacin acyl and ether glucuronide.