Metabolism of the Antituberculosis Drug Ethionamide

Vale, Nuno; Gomes, Paula; Santos, Hélder A.

doi:10.2174/13892002130113

Cited by 6 publications

(7 citation statements)

References 31 publications

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“…4 This bioactivation results in reactive S-oxide intermediate, 5 which bind to NAD + /NADH; forming adducts, thereby inhibiting the enoyl CoA reductase InhA. 6,7 Mammalian flavin-containing monooxygenase (FMO) is also active toward ETA, resulting in its bioactivation. 8 Bioactivation of drugs to reactive metabolites is an unfavorable process during drug metabolism.…”

Section: ■ Introductionmentioning

confidence: 99%

Kinetics and Mechanism of Bioactivation via S-Oxygenation of Anti-Tubercular Agent Ethionamide by Peracetic Acid

et al. 2016

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The kinetics and mechanism of the oxidation of the important antitubercular agent, ethionamide, ETA (2-ethylthioisonicotinamide), by peracetic acid (PAA) have been studied. It is effectively a biphasic reaction with an initial rapid first phase of the reaction which is over in about 5 s and a second slower phase of the reaction which can run up to an hour. The first phase involves the addition of a single oxygen atom to ethionamide to form the S-oxide. The second phase involves further oxidation of the S-oxide to desulfurization of ETA to give 2-ethylisonicotinamide. In contrast to the stability of most organosulfur compounds, the S-oxide of ETA is relatively stable and can be isolated. In conditions of excess ETA, the stoichiometry of the reaction was strictly 1:1: CHCOH + Et(CH)C(═S)NH → CHCOH + Et(CH)C(═NH)SOH. In this oxidation, it was apparent that only the sulfur center was the reactive site. Though ETA was ultimately desulfurized, only the S-oxide was stable. Electrospray ionization (ESI) spectral analysis did not detect any substantial formation of the sulfinic and sulfonic acids. This suggests that cleavage of the carbon-sulfur bond occurs at the sulfenic acid stage, resulting in the formation of an unstable sulfur species that can react further to form more stable sulfur species. In this oxidation, no sulfate formation was observed. ESI spectral analysis data showed a final sulfur species in the form of a dimeric sulfur monoxide species, HSO. We derived a bimolecular rate constant for the formation of the S-oxide of (3.08 ± 0.72) × 10 M s. Oxidation of the S-oxide further to give 2-ethylisonicotinamide gave zero order kinetics.

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Section: ■ Introductionmentioning

confidence: 99%

Kinetics and Mechanism of Bioactivation via S-Oxygenation of Anti-Tubercular Agent Ethionamide by Peracetic Acid

et al. 2016

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“…S‐oxygenation of ethionamide initially results in the formation of ethionamide S ‐oxide and, subsequently, a highly reactive sulfinic acid that spontaneously breaks down into 2‐ethyl‐4‐amidopyridine . As an active metabolite of ethionamide, the PBPK model of ethionamide S‐oxide was not considered along with its parent drug model in our study.…”

Section: Discussionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling Approach to Predict Drug‐Drug Interactions With Ethionamide Involving Impact of Genetic Polymorphism on FMO3

Nguyen

Parvez

Kim

et al. 2019

The Journal of Clinical Pharma

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The widely used second‐line antituberculosis drug ethionamide shows wide interindividual variability in its disposition; however, the relevant factors affecting this phenomenon have not been characterized. We previously reported the major contribution of flavin‐containing monooxygenase 3 (FMO3) in the reductive elimination pathway of ethionamide. In this study, ethionamide metabolism was potentially inhibited by methimazole in vitro. The drug‐drug interaction leading to methimazole affecting the disposition of ethionamide mediated by FMO3 was then quantitated using a bottom‐up approach with a physiologically based pharmacokinetic framework. The maximum concentration (Cmax) and area under the curve (AUC) of ethionamide were estimated to increase by 13% and 16%, respectively, when coadministered with methimazole. Subsequently, we explored the effect of FMO3 genetic polymorphism on metabolic capacity, by constructing 2 common functional variants, Lys158‐FMO3 and Gly308‐FMO3. Compared to the wild type, recombinant Lys158‐FMO3 and Gly308‐FMO3 variants significantly decreased the intrinsic clearance of ethionamide by 2% and 24%, respectively. Two prevalent functional variants of FMO3 were predicted to affect ethionamide disposition, with mean ratios of Cmax and AUC of up to 1.5 and 1.7, respectively, in comparison with the wild type. In comparing single ethionamide administration with the wild type, simulations of the combined effects of comedications and FMO3 genetic polymorphism estimated that the Cmax and AUC ratios of ethionamide increased up to 1.7 and 2.0, respectively. These findings suggested that FMO3‐mediated drug‐drug interaction and genetic polymorphism could be important determinants of interindividual heterogeneity in ethionamide disposition that need to be considered comprehensively to optimize the personalized dosing of ethionamide.

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“…Compounds belonging to this class can be converted to substituted isonicotinic acid derivatives in vivo, which can interfere with the synthesis of mycolic acids, thereby inhibiting the synthesis of the cell wall of mycobacterium tuberculosis. Furthermore, ETA is easily absorbed and widely distributed in the body …”

Section: Introductionmentioning

confidence: 99%

Design and scale‐up of an alkylated Minisci reaction to produce ethionamide with 4‐cyanopyridine as raw materials

Liang

Wang

et al. 2017

Can J Chem Eng

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Tuberculosis is a serious bacterial infection in developing countries, especially in areas with drug resistance. The development of the anti‐tuberculosis drug ethionamide (ETA) is therefore particularly important. We have designed a new route for ETA synthesis and considered the drug's amenability to large‐scale manufacture. We evaluated different routes for the synthesis of ETA and selected the most suitable process for the industrial production of this material, which involved the Minisci reaction of 4‐cyanopyridine with propionic acid using a AgNO3/(NH4)2S2O8 catalyst system under acidic conditions. The effects of different parameters on the reaction were studied, and the production of the intermediate of 2‐ethyl‐4‐cyanopyridine was twice recrystallized from methanol to obtain pure ETA. In the Minisci reaction, the system was stirred for an additional 20 min at 80 °C after the addition of ammonium persulphate solution. The subsequent formation of thioamide was conducted at 40 °C to 60 °C for 1.5 h with a 1:5:2 molar ratio of 4‐cyanopyridine, propionic acid, and ammonium sulphide. The purity of the crude ETA reached 98.77 % after two recrystallization steps. This process could be scaled up on a much larger scale (1 kg), leading to the yield of alkylation reaction and overall yield of the production process as 44.06 % and 31.26 %, respectively.

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Metabolism of the Antituberculosis Drug Ethionamide

Cited by 6 publications

References 31 publications

Kinetics and Mechanism of Bioactivation via S-Oxygenation of Anti-Tubercular Agent Ethionamide by Peracetic Acid

Kinetics and Mechanism of Bioactivation via S-Oxygenation of Anti-Tubercular Agent Ethionamide by Peracetic Acid

Physiologically Based Pharmacokinetic Modeling Approach to Predict Drug‐Drug Interactions With Ethionamide Involving Impact of Genetic Polymorphism on FMO3

Design and scale‐up of an alkylated Minisci reaction to produce ethionamide with 4‐cyanopyridine as raw materials

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