ENANTIOSELECTIVITY OF THE ENTEROHEPATIC RECYCLING OF CARPROFEN IN THEDOG

The disposition of the two enantiomers of carprofen (CPF), the (R)-CPF and the (S)-CPF, was investigated after iv administration of the race mate (4 mg/kg) in dogs equipped with a chronic bile duct catheter. Stu dies in dogs with diverted bile flow showed that both enantiomers were extensively excreted in bile with 74% of the (R)-enantiomer and 92% o f the (S)-enantiomer from the iv administered dose being recovered in the bile as the respective glucuronide conjugates. The direct administ ration of acidic bile containing acyl-glucuronides of CPF in the duode num showed that both conjugated enantiomers led to high CPF enantiomer systemic availability. However, comparison of CPF pharmacokinetics be tween dogs with nondiverted bile flow and dogs with diverted bile flow suggested that CPF was subjected to enantioselective enterohepatic re cycling (EHC) and that only the (S)-CPF was recycled. The absence of E HC for the (R)-CPF is hypothesized to be the result of formation of gl ucuronidase-resistant isoglucuronides (epimers) to a greater extent fo r the (R)-CPF than for the (S)-CPF.