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

Vladimír Kubíček,Lenka Skálová,Zdeněk Šubrt,Jana Holubová,Adam Skarka,Věra Králová,Jana Štěpánková,Barbora Szotáková

doi:10.3389/fphar.2019.00600

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.

Highlights

Anthelmintic drugs of the benzimidazole type are often used in human and veterinary medicine
The in vitro biotransformation studies of FLU with pooled human liver cytosolic and microsomal fractions were designed to determine the preference of coenzymes for FLU reduction and stereospecificity of this process
FLU reduction was highest in the cytosol with the nicotinamide adenine dinucleotide phosphate (NADPH) coenzyme; on the other hand, in microsomal fraction with NADH coenzyme, no FLUR was detected (Table 1)

Summary

Introduction

Anthelmintic drugs of the benzimidazole type are often used in human and veterinary medicine They have broad anthelmintic activity, low toxicity, and, a small incidence of undesirable effects. The mechanism of their action is based on specific binding to the microtubule subunit tubulin, resulting in the disruption of the microtubule structure and the inhibition of secretory vesicle transport. These anthelmintics inhibit glucose uptake, exhaust glycogen stores, and prevent ATP formation, leading to the death of the helminth. Because FLU has been registered in Europe for treatment of gut-residing nematodes in humans (Mackenzie and Geary, 2011), its repurposing could be expected soon

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