ABSTRACT
The influence of clofibrate on the stereoconversion of fenoprofen (FPF) was studied in guinea pigs. This hypolipidaemic agent has been related to some biochemical changes in the liver leading to an increase in the chiral inversion process. Two groups of animals (n = 6 per group) were pretreated with oral doses of clofibrate (280 mg/kg per day) for three days and were then given (R)- or (S)-FPF (5 mg/kg, IV). The FPF enantiomers were extracted from the guinea-pigs' plasma using a solid phase procedure and analysed by HPLC with previous derivatization with L-leucinamide. Pretreatment with clofibrate increased the chiral inversion of (R)-FPF in favour of the pharmacologically active (S)-FPF enantiomer. Before this metabolic interaction can be applied to therapy with fenoprofen, the toxic effects of (S)-(+)-FPF on the gastrointestinal and renal tracts and the interference by (R)-(-)-FPF with the metabolism of lipids should be thoroughly evaluated.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Clofibrate/pharmacology , Fenoprofen/chemistry , Fenoprofen/pharmacokinetics , Animals , Anti-Inflammatory Agents, Non-Steroidal/blood , Area Under Curve , Biotransformation/drug effects , Chromatography, High Pressure Liquid , Clofibrate/administration & dosage , Fenoprofen/blood , Guinea Pigs , Liver/drug effects , Liver/enzymology , Liver/metabolism , Male , Molecular Structure , Stereoisomerism , Time FactorsABSTRACT
Suprofen (SPF) is a non-steroidal anti-inflammatory drug (NSAID), which belongs to the 2-arylpropionic acids subclass. As a result of their chiral characteristics, these compounds have shown a marked enantioselective behaviour with a high degree of interspecies variation. They are mainly eliminated by glucuronidation. Plasma, biliary and urine disposition of SPF was investigated in the cat after intravenous administration of the racemate (dose 2 mg/kg). Both enantiomers exhibited similar disposition profiles in plasma with no evidence of chiral inversion. During bile sampling time, recovered acylglucuronides of R (-) and S (+) SPF were less than 1% of the total dose administered. Only free SPF was recovered in the urine, representing 0.12% of the administered racemic SPF dose. The results indicate that neither chiral inversion nor glucuronidation predominate in SPF disposition in cats.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Cats/metabolism , Suprofen/pharmacokinetics , Animals , Anti-Inflammatory Agents, Non-Steroidal/blood , Anti-Inflammatory Agents, Non-Steroidal/urine , Bile/metabolism , Isomerism , Male , Species Specificity , Suprofen/blood , Suprofen/urineABSTRACT
The chiral inversion process is a characteristic metabolic pathway for different aryl-2-propionic acids or profens. Important variations have been observed between these individual compounds as well as between animal species. In this study, R(-) fenoprofen [R(-)FPF] and R(-) ketoprofen [R(-) KTF] were used to investigate their comparative stereoconversion in cats. After intravenous (i.v.) administration of R(-) FPF, the percentage of chiral inversion was 93.20+/-13.70%. A highly significant correlation (r: 0.978) was observed between the clearance of R(-) FPF and the chiral inversion process. After i.v. administration of R(-) KTF, the percentage of inversion was only 36.73+/-2.8%. No correlation between the clearance of R(-) KTF and this process was observed. R(-) FPF was metabolized by the pathways of thioesterification - chiral inversion processes. For R(-) KTF, the competitive metabolic pathways, glucuronidation and hydroxylation may be involved. However, these metabolic steps are saturable or less functional in cats. Moreover, the thioesterification of R(-) KTF in in vitro studies has been shown to be important in carnivores. The lack of correlation between clearance and chiral inversion process of R(-) KTF may be finally explained by deviation of thioesterification to other metabolic pathways of lipids and/or aminoacid conjugation, particulary glicine derivatives.
