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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00600

Carbonyl reduction of flubendazole in the human liver: strict stereospecificity, sex-difference, low risk of drug interactions

 Vladimír Kubíček1, Lenka Skálová2, Adam Skarka3, Věra Králová4, Jana Holubová2, Jana Štěpánková2, Zdeněk Šubrt5 and  Barbora Szotáková2*
  • 1Department of Biophysics and Physical Chemistry, Charles University, Czechia
  • 2Department of Biochemical Sciences, Charles University, Czechia
  • 3Department of Chemistry, University of Hradec Králové, Czechia
  • 4Department of Biology, Charles University, Czechia
  • 5Department of Surgery, Fakultní Nemocnice Hradec Králové, Czechia

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, as this information has been insufficient until now. Subcellular fractions from the liver of 12 human patients (6 males and 6 females) 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 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 was found in males than in females, 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.

Keywords: flubendazole, Carbonyl reduction, human, enzyme kinetics, Stereospecificity, Sex-difference

Received: 26 Feb 2019; Accepted: 10 May 2019.

Edited by:

Olavi R. Pelkonen, University of Oulu, Finland

Reviewed by:

John M. Rimoldi, University of Mississippi, United States
Massimo Valoti, University of Siena, Italy  

Copyright: © 2019 Kubíček, Skálová, Skarka, Králová, Holubová, Štěpánková, Šubrt and Szotáková. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Barbora Szotáková, Charles University, Department of Biochemical Sciences, Prague, 116 36, Prague, Czechia, szotakova@faf.cuni.cz