Chromatographic resolution of ciprofibrate and interaction of the racemate and both enantiomers with rat liver microsomes in vitro.
The enantiomers of ciprofibrate may be achieved by enantioselective HPLC separation of its methylesters using a OD - Daicel column. Ciprofibrates (racemate and both enantiomers) bind to oxidized cytochrome P-450 in rat liver microsomes according type II like aniline or most probably as inversed type I, but less pronounced and with a general shift to the left. Ethylmorphine N-demethylation, ethoxycoumarin and ethoxyresorufin O-deethylation are all inhibited by the ciprofibrates, most effectively ethoxyresorufin O-deethylation by S(-)-ciprofibrate even in microM concentrations. Microsomal luminol and lucigenin amplified chemiluminescence indicating the formation of reactive oxygen species, microsomal hydrogen peroxide formation and NADPH/Fe stimulated lipid peroxidation were inhibited in a concentration dependent manner in concentration ranges between mM and microM. This might be due to distinct scavenger activities of all 3 compounds: the zymosan stimulated chemiluminescence of whole blood was completely inhibited in mM concentrations and influenced significantly down to concentrations of 10 microM, whereas burst and phagocytosis tests with human polynuclear leucocytes were not influenced.
Institut für Pharmazie, Friedrich-Schiller-Universität Jena, Germany.
H
H
Oelschläger
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D
Rothley
W
W
Klinger
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E
Karge
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Vogelsang
D000814:Aniline Compounds / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D058607:Fibric Acids; D006591:Hexobarbital / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species; D016897:Respiratory Burst / Q000187:drug effects; D013237:Stereoisomerism
D000814:Aniline Compounds; D058607:Fibric Acids; D000960:Hypolipidemic Agents; D017382:Reactive Oxygen Species; D002995:Clofibric Acid; D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital; D006861:Hydrogen Peroxide; C019304:ciprofibrate; C023650:aniline