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Carbonyl Reduction of Flubendazole in the Human Liver: Strict Stereospecificity, Sex Difference, Low Risk of Drug Interactions

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dc.contributor.author Kubicek, Vladimir cze
dc.contributor.author Skalova, Lenka cze
dc.contributor.author Skarka, Adam cze
dc.contributor.author Kralova, Vera cze
dc.contributor.author Holubova, Jana cze
dc.contributor.author Stepankova, Jana cze
dc.contributor.author Subrt, Zdenek cze
dc.contributor.author Szotakova, Barbora cze
dc.date.accessioned 2019-10-17T07:25:09Z
dc.date.available 2019-10-17T07:25:09Z
dc.date.issued 2019 eng
dc.identifier.issn 1663-9812 eng
dc.identifier.uri http://hdl.handle.net/20.500.12603/53
dc.description.abstract Flubendazole (FLU), an anthelmintic drug of benzimidazole type, is now considered a promising anti-cancer agent due to its tubulin binding ability and low system toxicity. The present study was aimed at determining more information about FLU reduction in human liver, because this information has been insufficient until now. Subcellular fractions from the liver of 12 human patients (6 male and 6 female patients) were used to study the stereospecificity, cellular localization, coenzyme preference, enzyme kinetics, and possible inter-individual or sex differences in FLU reduction. In addition, the risk of FLU interaction with other drugs was evaluated. Our study showed that FLU is predominantly reduced in cytosol, and the reduced nicotinamide adenine dinucleotide phosphate (NADPH) coenzyme is preferred. The strict stereospecificity of FLU carbonyl reduction was proven, and carbonyl reductase 1 was identified as the main enzyme of FLU reduction in the human liver. A higher reduction of FLU and a higher level of carbonyl reductase 1 protein were found in male patients than in female patients, but overall inter-individual variability was relatively low. Hepatic intrinsic clearance of FLU is very low, and FLU had no effect on doxorubicin carbonyl reduction in the liver and in cancer cells. All these results fill the gaps in the knowledge of FLU metabolism in human. eng
dc.format p. 1-9 eng
dc.language.iso eng eng
dc.publisher FRONTIERS MEDIA SA eng
dc.relation.ispartof FRONTIERS IN PHARMACOLOGY, volume 10, issue: MAY eng
dc.rights Práce není přístupná eng
dc.subject flubendazole eng
dc.subject carbonyl reduction eng
dc.subject human eng
dc.subject enzyme kinetics eng
dc.subject stereospecificity eng
dc.subject sex difference eng
dc.subject flubendazol cze
dc.subject redukce karbonylu cze
dc.subject člověk cze
dc.subject enzymová kinetika cze
dc.subject stereospecificita cze
dc.subject rozdíl pohlaví cze
dc.title Carbonyl Reduction of Flubendazole in the Human Liver: Strict Stereospecificity, Sex Difference, Low Risk of Drug Interactions eng
dc.title.alternative Karbonylová redukce flubendazolu v lidských játrech: přísná stereotypnost, rozdíly v pohlaví, nízké riziko lékových interakcí cze
dc.type article eng
dc.identifier.obd 43875242 eng
dc.identifier.wos 000469265800001 eng
dc.identifier.doi 10.3389/fphar.2019.00600 eng
dc.description.abstract-translated Flubendazole (FLU), an anthelmintic drug of benzimidazole type, is now considered a promising anti-cancer agent due to its tubulin binding ability and low system toxicity. The present study was aimed at determining more information about FLU reduction in human liver, because this information has been insufficient until now. Subcellular fractions from the liver of 12 human patients (6 male and 6 female patients) were used to study the stereospecificity, cellular localization, coenzyme preference, enzyme kinetics, and possible inter-individual or sex differences in FLU reduction. In addition, the risk of FLU interaction with other drugs was evaluated. Our study showed that FLU is predominantly reduced in cytosol, and the reduced nicotinamide adenine dinucleotide phosphate (NADPH) coenzyme is preferred. The strict stereospecificity of FLU carbonyl reduction was proven, and carbonyl reductase 1 was identified as the main enzyme of FLU reduction in the human liver. A higher reduction of FLU and a higher level of carbonyl reductase 1 protein were found in male patients than in female patients, but overall inter-individual variability was relatively low. Hepatic intrinsic clearance of FLU is very low, and FLU had no effect on doxorubicin carbonyl reduction in the liver and in cancer cells. All these results fill the gaps in the knowledge of FLU metabolism in human. cze
dc.publicationstatus postprint eng
dc.peerreviewed yes eng


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