SPECIES-DEPENDENT ENANTIOSELECTIVE GLUCURONIDATION OF CARPROFEN

1. The stereoselective glucuronidation of carprofen, a non-steroidal a nti-inflammatory drug, was investigated in vitro using microsomes prep ared from liver of different species (rat, dog, horse, sheep and man) or UGT2B1 expressed in fibroblasts. 2. The K-m towards the drug was ve ry similar among these species and for the two enantiomers, whereas th e V-max varied substantially according to the animal used. The rat exh ibited a high stereoselective glucuronidation whereas other species, i ncluding 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 enantio selective 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 pharmacokinetic parameters AUCs. The basic hypothesi s that the intrinsic clearance reflect the enantioselective behaviour of carprofen seemed substantiated when we focused on man and rat glucu ronidation, but the in vivo-in vitro correlation was not possible in o ther species. 4. In conclusion, the chiral pharmacokinetics of carprof en is less dependent on the stereoselective glucuronidation than other stereoselective processes such as protein binding of carprofen, enzym atic hydrolysis, or renal elimination of glucuronides.