Species-dependent enantioselective glucuronidation of carprofen

Abstract

1. The stereoselective glucuronidation of carprofen, a non-steroidal anti-inflammatory drug, was investigated in vitro using microsomes prepared from liver of different species (rat, dog, horse, sheep and man) or UGT2B1 expressed in fibroblasts. 2. The K_m towards the drug was very similar among these species and for the two menantiomers, whereas the V_max varied substantially according to the animal used. The rat exhibited a high stereoselective glucuronidation whereas other species, including man, presented a low stereoselectivity. The R-enantiomer was glucuronidated at a more efficient rate than its enantiomorph, and was a better substrate (in terms of V_max/K_m). 3. To explain the enantioselective disposition of carprofen in man and in the different species,the ratio of the enzymatic efficacies (V_max/K_m) were compared with the ratio of the max m pharmacokinetic parameters AUCs. The basic hypothesis that the intrinsic clearance reflect the enantioselective behaviour of carprofen seemed substantiated when we focused onmanand rat glucuronidation,but the in vivo-in vitro correlationwas not possibleinother species. 4. In conclusion, the chiral pharmacokinetics of carprofen is less dependent on the stereoselective glucuronidationthanotherstereoselective processes such as protein binding of carprofen, enzymatic hydrolysis, or renal elimination of glucuronides.