Transport and Biotransformation of Gliclazide and the Effect of Deoxycholic Acid in a Probiotic Bacteria Model

Abstract

Introduction: Inter-individual differences in gut microflora composition may affect drug metabolism and overall therapeutic response. Gliclazide is a drug characterized by large inter-individual differences in therapeutic response; however, the causes of these differences are not fully explained and may be the outcome of microbial biotransformation. Recently, great attention has been paid to studies on bile acid (BA) interactions with gut microflora and the role of BAs in the modification of drug transport through biological membranes.The Aim: Considering the assumption of gliclazide–probiotic–BAs interactions, the aim of the study was to investigate the transport and biotransformation of gliclazide in probiotic bacteria, as well as the effects of deoxycholic acid (DCA) on gliclazide transport into bacterial cells.Materials and Methods: Probiotics were incubated with gliclazide with or without DCA for 24 h at 37°C. The intracellular and extracellular concentrations of gliclazide were determined at seven time points by high-performance liquid chromatography. Gliclazide biotransformation by the enzymatic activity of probiotic bacteria was examined using appropriate software packages.Results: During the 24 h incubation with probiotic bacteria, significantly lower extracellular concentrations of gliclazide were observed at all time points compared to controls, while in the group with DCA, the decrease in concentration was noticed only at 24 h. The total concentration of gliclazide throughout the whole period was significantly lower compared to control. Proposed pathways of gliclazide biotransformation by probiotic bacteria involve reactions of hydrolysis and hydroxylation.Conclusion: Based on the results obtained, it can be concluded that there are interactions of gliclazide–probiotics–DCA, at both the level of active and passive transport into the cells, and at the level of drug biotransformation by enzymatic activity of probiotic bacteria. The effect of these interactions on the final therapeutic response of gliclazide should be further studied and confirmed in in vivo conditions.

Bioaccumulation and biotransformation of simvastatin in probiotic bacteria: A step towards better understanding of drug-bile acids-microbiome interactions

“…Beyond the increasingly recognized scenario of biotransformation by the bacterial enzymes, in a previously published study, we have demonstrated that drugs may also accumulate in gut bacteria ( Đanić et al, 2019 ). To the best of our knowledge, no previous research had considered drug-bacteria interactions in terms of bioaccumulation so this type of interaction is a completely new aspect that needs special attention in future studies to gain a more in-depth understanding of its influence on drug bioavailability.…”

“…The tubes were incubated at anaerobic conditions at 37°C for 24 h, gently shaking the tubes occasionally. Extracellular and intracellular medium samples were collected and prepared for the LC-MS analysis at predetermined time points (0 min, 15 min, 1 h, 2 h, 4 h, 6 h, 24 h) according to previously published procedure ( Đanić et al, 2019 ). In each time point, after the gentle shaking the tubes to uniformly distribute the content, 100 μL of samples were withdrawn and centrifuged for 5 min at 15,000 rpm to precipitate bacteria.…”

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“…В настоящее время выявляются все новые факторы, влияющие на вариабельность гликемии. Так, появились данные о вовлечении в процесс гликолиза и гидролиза гликлазида кишечной микрофлоры, индивидуальность взаимодействия которой с пробиотиками, например, дезоксихолевой кислотой, определяет индивидуальность действия ПСМ и нивелирование высокой вариабельности гликемии [18]. Установлено также, что представители класса ПСМ, за исключением гликлазида, оказывают влияние на рецепторы, активируемые пероксисомными пролифераторами γ PRRAγ, способствуя набору массы тела [19].…”

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“…The secondary bile acid, DCA, is known for its ability to increase membrane permeability in various physiological settings [ 159 , 160 , 161 , 162 ]. A study by Lalić-Popović et al [ 159 ] investigated the effects of DCA on the permeability of gliclazide across the blood–brain barrier in healthy and diabetic rats.…”