CLINICAL PHARMACOLOGY
Absorption
Ethionamide is essentially completely absorbed following oral administration and is not subjected to any appreciable first pass metabolism. Ethionamide tablets may be administered without regard to the timing of meals.
The pharmacokinetic parameters of ethionamide following single oral-dose administration of 250 mg of Trecator film-coated tablets under fasted conditions to 40 healthy adult volunteers are provided in Table 1.
| Cmax (µg/mL) | Tmax (hrs) | AUC (µg∙hr/mL) | |
|---|---|---|---|
| Film-Coated Tablet | 2.16 (0.61) | 1.02 (0.55) | 7.67 (1.69) |
Trecator tablets have been reformulated from a sugar-coated tablet to a film-coated tablet. The Cmax for the film-coated tablets (2.16 µg/mL) was significantly higher than that of sugar-coated tablets (1.48 µg/mL) (see DOSAGE AND ADMINISTRATION).
Distribution
Ethionamide is rapidly and widely distributed into body tissues and fluids following administration of a sugar-coated tablet, with concentrations in plasma and various organs being approximately equal. Significant concentrations are also present in cerebrospinal fluid following administration of a sugar-coated tablet. Distribution of ethionamide into the same body tissues and fluids, including cerebrospinal fluid following administration of the film-coated tablet, has not been studied, but is not expected to differ significantly from that of the sugar-coated tablet. The drug is approximately 30% bound to proteins. The mean (SD) apparent oral volume of distribution observed in 40 healthy volunteers following a 250 mg oral dose of film-coated tablets was 93.5 (19.2) L.
Metabolism
Ethionamide is extensively metabolized to active and inactive metabolites. Metabolism is presumed to occur in the liver and thus far 6 metabolites have been isolated: 2-ethylisonicotinamide, carbonyl-dihydropyridine, thiocarbonyl-dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioiso-nicotinamide, and ethionamide sulphoxide. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis.
Elimination
The mean (SD) half-life observed in 40 healthy volunteers following a 250 mg oral dose of film-coated tablets was 1.92 (0.27) hours. Less than 1% of the oral dose is excreted as ethionamide in urine.
Mechanism of Action
Ethionamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. The exact mechanism of action of ethionamide has not been fully elucidated, but the drug appears to inhibit peptide synthesis in susceptible organisms.
Microbiology
In Vitro Activity
Ethionamide exhibits bacteriostatic activity against extracellular and intracellular Mycobacterium tuberculosis organisms. The development of ethionamide resistant M. tuberculosis isolates can be obtained by repeated subculturing in liquid or on solid media containing increasing concentrations of ethionamide. Multi-drug resistant strains of M. tuberculosis may have acquired resistance to both isoniazid and ethionamide. However, the majority of M. tuberculosis isolates that are resistant to one are usually susceptible to the other. There is no evidence of cross-resistance between ethionamide and para-aminosalicylic acid (PAS), streptomycin, or cycloserine. However, limited data suggest that cross-resistance may exist between ethionamide and thiosemicarbazones (i.e., thiacetazone) as well as isoniazid.
In Vivo Activity
Ethionamide administered orally initially decreased the number of culturable Mycobacterium tuberculosis organisms from the lungs of H37Rv infected mice. Drug resistance developed with continued ethionamide monotherapy, but did not occur when mice received ethionamide in combination with streptomycin or isoniazid.