Metabolism and Pharmacokinetics of the Anti-Tuberculosis Drug Ethionamide in a Flavin-Containing Monooxygenase Null Mouse

Abstract

Multiple drug resistance (MDR) in Mycobacterium tuberculosis (mTB), the causative agent for tuberculosis (TB), has led to increased use of second-line drugs, including ethionamide (ETA). ETA is a prodrug bioactivated by mycobacterial and mammalian flavin-containing monooxygenases (FMOs). FMO2 is the major isoform in the lungs of most mammals, including primates. In humans a polymorphism exists in the expression of FMO2. FMO2.2 (truncated, inactive) protein is produced by the common allele, while the ancestral allele, encoding active FMO2.1, has been documented only in individuals of African and Hispanic origin, at an incidence of up to 50% and 7%, respectively. We hypothesized that FMO2 variability in TB-infected individuals would yield differences in concentrations and ratios of ETA prodrug and metabolites. In this study we assessed the impact of the FMO2 genetic polymorphism on the pharmacokinetics of ETA after administration of a single oral dose of ETA (125 mg/kg) to wild type and triple Fmo1/2/4-null mice, measuring levels of prodrug vs. metabolites in plasma collected from 0 to 3.5 h post-gavage. All mice metabolized ETA to ETA S-oxide (ETASO) and 2-ethyl-4-amidopyridine (ETAA). Wild type mice had higher plasma concentrations of metabolites than of parent compound (p = 0.001). In contrast, Fmo1/2/4-null mice had higher plasma concentrations of parent compound than of metabolites (p = 0.0001). Thus, the human FMO2 genotype could impact the therapeutic efficacy and/or toxicity of ETA.

Drug metabolism by flavin-containing monooxygenases of human and mouse

“…Adverse behavioural changes, such as tremor, were observed only in mice that lacked FMO1 (the knockout mice), which produced higher amounts in brain of desipramine, a product of CYP-mediated metabolism. ) was used to better mimic the situation in human, with respect to expression of FMOs in lung, and to establish whether a lack of FMO2 influences the metabolism of ethionamide in vivo [122]. The plasma concentration of ethionamide was found to be higher in knockout than in wild-type mice and that of ethionamide S-oxide to be higher in wild-type than in knockout animals, confirming the involvement of FMO2…”

Pharmacokinetics of Ethionamide Delivered in Spray-Dried Microparticles to the Lungs of Guinea Pigs

“…The first step in ETH metabolism is transformation to sulphoxide metabolites, which have antimicrobial activity, by Flavin-containing-monooxygenases (FMO) 25 . From the five functional FMOs, the isoforms 1, 2 and 3 are implicated in the metabolism of ETH: FMO1 is primarily expressed in liver, kidney and intestine; FMO2 is the major isoform in the lungs and FMO3 is the primary FMO in the liver 45 . There are no reports of the expression and localization of FMOs in the guinea pig but it is plausible that they would be located in the same organs as in man.…”

Flavin-containing monooxygenase S-oxygenation of a series of thioureas and thiones

“…This finding is important, given that ethionamide is a prodrug and is bioactivated through the sulfinic acid by a similar monooxygenase found in Mycobacterium tuberculosis (Dover et al, 2007; Hannoulle et al, 2006). Our laboratory has recently found mice, null for Fmo2 expression, exhibit markedly lower ratios of ethionamide sulfoxide/ethionamide in plasma (Palmer et al, 2012) and pulmonary lavage fluid (Singh et al, unpublished) following dosing with this anti-tuberculosis prodrug. Taken together, these data suggest that the genetic polymorphism in expression of hFMO2 may have a number of consequences with respect to the toxicity and/or therapeutic efficacy of drugs containing a thiocarbamide or related structural moiety in the lung.…”