Moment analysis of stereoselective biliary excretion and chiral inversion of ketoprofen enantiomers in perfused rat liver.
The stereoselective local disposition of ketoprofen was evaluated by the single-pass perfusion experiment following a bolus injection of R(-)- or S(+)-ketoprofen into the liver from the portal vein. The elution time profiles of enantiomers into the hepatic vein and the excretion time profiles into the bile were kinetically assessed by local moment analysis. The hepatic recovery ratios (FH) of both enantiomers were < 1%, and the mean hepatic transit times (tH) were approximately 7 s. After the injection of S-ketoprofen into the liver, the biliary excretion ratio (Fb) of total S-ketoprofen was 68% (15% S-ketoprofen and 53% glucuronide) and the mean biliary transit time (tb) of S-ketoprofen was 10 min. R-Ketoprofen inversion from S-ketoprofen was not observed in either the perfusate or in the bile. After the injection of R-ketoprofen, the Fb of total R-ketoprofen was 12% (3% R-ketoprofen and 9% glucuronide), and tb of R-ketoprofen was 8 min. The Fb of total S-ketoprofen inverted from R-ketoprofen was 24% (7% S-ketoprofen and 17% glucuronide), and the tb of inverted S-ketoprofen was 17 min. Forty-six percent of R-ketoprofen was inverted to S-ketoprofen during a single pass through the rat liver, and the mean inversion time was 7.5 min. It was concluded that the unidirectional chiral inversion of ketoprofen was stereospecific, and the hepatic uptake and biliary excretion were stereo-nonspecific.
Yasui
H
H
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Yamaoka
K
K
Dote
N
N
Nakagawa
T
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D066298:In Vitro Techniques; D007660:Ketoprofen / Q000737:chemistry / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007660:Ketoprofen