GLUCURONIDATION OF PROPOFOL IN MICROSOMAL FRACTIONS FROM VARIOUS TISSUES AND SPECIES INCLUDING HUMANS - EFFECT OF DIFFERENT DRUGS

This in vitro study was conducted to evaluate propofol glucuronidation and the effect of concomitantly administered drugs in various species . Propofol glucuronidation was studied in microsomal fractions from ra t, rabbit, and human livers. Extrahepatic metabolism was investigated using lung and kidney microsomes. The propofol-uridine diphosphate-glu curonosyltransferase (UGT) activity measured in liver microsomes was h igher in rabbit than in rat. Among the three tested species, human Liv ers exhibited the highest activity, with only small variability in the three samples studied. Animal kidney, but not lung (animal or human), microsomes were able to glucuronidate propofol, meaning that extrahep atic metabolism of propofol exists, at least in the kidney, in the tes ted species (rat and rabbit). Since metabolic interactions are potenti al sources of prolonged drug effect or overdose, we screened the effec t of 21 compounds (known substrates of various UGT or potentially coad ministered drugs) on the glucuronidation of propofol by human liver mi crosomes. inhibitions obtained with chemicals or drugs glucuronidated by either UGT1 or UGT2 families (1-naphtol, 4-hydroxybiphenyl, carvacr ol, n-propylgallate, ketoprofen, chloramphenicol, acetylsalicylic acid ) indicated that at least two UGT isoforms are involved in propofol gl ucuronidation. Inhibition was observed with several drugs potentially coadministered during pre-, per-, or postoperative periods (e.g., acet ylsalicylic acid, ketoprofen, oxazepam, fentanyl). Although not direct ly transposable to the in vivo situation, these results indicate that such interactions are theoretically possible. Similarly, the inhibitor y effect of fentanyl on propofol glucuronidation demonstrated by our i n vitro study could explain the in vivo drug-drug interaction that has been described for this drug. Nine other widely used drugs had no eff ect on in vitro propofol glucuronidation.