Moment Analysis of Stereoselective Enterohepatic Circulation and Unidirectional Chiral Inversion of Ketoprofen Enantiomers in Rat

Abstract

The stereoselective enterohepatic circulation (EHC) and the synchronous chiral inversion of ketoprofen enantiomer in rat were evaluated by moment analysis based on the recirculatory concept. (R)-(−)- and (S)-(+)-ketoprofen were independently administered into rats, and the plasma and bile concentrations of both enantiomers were determined by a column-switching HPLC. (S)-Ketoprofen was generated by the chiral inversion from (R)-ketoprofen, whereas (R)-ketoprofen was not generated from (S)-ketoprofen. Within 30min after intravenous administrations, the plasma time courses of R- and S-enantiomers were almost the same between rats with laparotomy and those with bile-duct cannula. After 30 min, the plasma concentrations in rats with laparotomy were significantly higher than those in rats with bile-duct cannula. The Laplace-transformed equations for stereoselective EHC and the synchronous chiral inversion were derived by means of the transfer function method on the basis of the recirculatory theory. The global moments (AUC and MRT) which were derived directly from the transformed equations were related to the local moments for the single EHC. The recirculation ratios of (R)- and (S)-ketoprofen for the single EHC were estimated to be 15.4% and 63.6%, respectively. The absorption ratios of (R)- and (S)-ketoprofen for the absorption process from the gastrointestinal tract into the systemic circulation were 87.0% and 83.8%, respectively. The biliary excretion ratios of (R)- and (S)-ketoprofen for the disposition process through the systemic circulation into the bile were 17.7% and 75.8%, respectively. The chiral inversion ratio from (R)-ketoprofen into (S)-ketoprofen was 59.5%. The complicated disposition of ketoprofen, i.e., the simultaneous EHC and chiral inversion, was able to be analyzed by a moment method in a simple way.