title: Inhibition of 1,4-butanediol metabolism in human liver in vitro.
abstract: The conversion of 1,4-butanediol (1,4-BD) to gamma-hydroxybutyric acid (GHB), a drug of abuse, is most probably catalyzed by alcohol dehydrogenase, and potentially by aldehyde dehydrogenase. The purpose of this study was to investigate the degradation of 1,4-BD in cytosolic supernatant of human liver in vitro, and to verify involvement of the suggested enzymes by means of gas chromatography-mass spectrometry. The coingestion of 1,4-BD and ethanol (EtOH) might cause complex pharmacokinetic interactions in humans. Therefore, the effect of EtOH on 1,4-BD metabolism by human liver was examined in vitro. Additionally, the influence of acetaldehyde (AL), which might inhibit the second step of 1,4-BD degradation, was investigated. In case of a 1,4-BD intoxication, the alcohol dehydrogenase inhibitor fomepizole (4-methylpyrazole, FOM) has been discussed as an antidote preventing the formation of the central nervous system depressing GHB. Besides FOM, we tested pyrazole, disulfiram, and cimetidine as possible inhibitors of the formation of GHB from 1,4-BD catalyzed by human liver enzymes in vitro. The conversion of 1,4-BD to GHB was inhibited competitively by EtOH with an apparent K(i) of 0.56 mM. Therefore, the coingestion of 1,4-BD and EtOH might increase the concentrations and the effects of 1,4-BD itself. By contrast AL accelerated the formation of GHB. All antidotes showed the ability to inhibit the formation of GHB. In comparison FOM showed the highest inhibitory effectiveness. Furthermore, the results confirm strong involvement of ADH in 1,4-BD metabolism by human liver.
authors.affiliation: Institute of Legal Medicine, University Hospital of Cologne, Melatengürtel 60-62, 50823 Cologne, Germany. daniel.lenz@uk-koeln.de
authors.forename: Daniel
authors.initials: D
authors.lastname: Lenz
authors.forename: Martin
authors.initials: M
authors.lastname: Jübner
authors.forename: Katja
authors.initials: K
authors.lastname: Bender
authors.forename: Annette
authors.initials: A
authors.lastname: Wintermeyer
authors.forename: Justus
authors.initials: J
authors.lastname: Beike
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rothschild
authors.forename: Herbert
authors.initials: H
authors.lastname: Käferstein
mesh_terms: D000328:Adult; D000368:Aged; D000931:Antidotes / Q000494:pharmacology; D002072:Butylene Glycols / Q000378:metabolism*; D002927:Cimetidine / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D000077604:Fomepizole; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006801:Humans; D006885:Hydroxybutyrates / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000494:pharmacology*
chemical_list: D000931:Antidotes; D002072:Butylene Glycols; D006885:Hydroxybutyrates; D011720:Pyrazoles; C111420:4-hydroxybutyric acid; D000431:Ethanol; C031280:pyrazole; C039681:1,4-butanediol; D002927:Cimetidine; D000077604:Fomepizole; D004221:Disulfiram