Species-dependent enantioselective glucuronidation of carprofen

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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 Km towards the drug was very similar among these species and for the two enantiomers, whereas the Vmax 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 Vmax/Km). 3. To explain the enantioselective disposition of carprofen in man and in the different species, the ratio of the enzymatic efficacies (Vmax/Km) were compared with the ratio of the pharmacokinetic parameters AUCs. The basic hypothesis that the intrinsic clearance reflect the enantioselective behaviour of carprofen seemed substantiated when we focused on man and rat glucuronidation, but the in vivo-in-vitro correlation was not possible in other species. 4. In conclusion, the chiral pharmacokinetics of carprofen is less dependent on the stereoselective glucuronidation than other stereoselective processes such as protein binding of carprofen, enzymatic hydrolysis, or renal elimination of glucuronides.