에티온아마이드 C화학적 특성, 용도, 생산
개요
Ethionamide is an antimycobacterial compound that is active against
M. tuberculosis (MICs = 0.3-1.25 μg/ml). It is activated
via oxidation by flavin monooxygenase and inhibits the InhA enzyme involved in mycolic acid biosynthesis. Formulations containing ethionamide have been used in the second-line treatment of multi-drug resistant tuberculosis.
화학적 성질
Yellow Solid
용도
Ethionamide is used in antimicrobials and in potency assay of test compounds on
M. tuberculosis.
Indications
Ethionamide (Trecator) is a derivative of isonicotinic
acid and is chemically related to isoniazid. It is a secondary
agent used in combination when primary agents
are ineffective or contraindicated; it is a bacteriostatic
antituberculosis agent. Its exact mechanism of action
is unknown but is believed to involve inhibition of
oxygen-dependent mycolic acid synthesis. It is thought
that mutations in the region of the (inhA) gene that are
involved in mycolic acid synthesis can cause both isoniazid
and ethionamide resistance.
정의
ChEBI: A thiocarboxamide that is pyridine-4-carbothioamide substituted by an ethyl group at position 2. A prodrug that undergoes metabolic activation by conversion to the corresponding S-oxide.
일반 설명
Yellow crystals or canary yellow powder with a faint to moderate sulfide odor.
공기와 물의 반응
Insoluble in water.
반응 프로필
A thiocarbamate/amine. Thiocarbamates slowly decompose in aqueous solution to form carbon disulfide and methylamine or other amines. Such decompositions are accelerated by acids. Flammable gases are generated by the combination of thiocarbamates and dithiocarbamates with aldehydes, nitrides, and hydrides. Thiocarbamates and dithiocarbamates are incompatible with acids, peroxides, and acid halides.
화재위험
Flash point data for Ethinamide are not available. Ethinamide is probably combustible.
Mechanism of action
Evidence has been presented suggesting that the mechanism of action of ethionamide is similar to that of INH. Similar to INH, ethionamide is considered to be a pro-drug, which is converted via oxidation by catalase-peroxidase to an active acylating agent, ethionamide sulfoxide, which in turn inactivates the inhA enoyl reductase enzyme. In the case of ethionamide, it has been proposed that the ethionamide sulfoxide acylates Cys-243 in inhA protein.
Pharmacology
Ethionamide is well absorbed following oral administration.
It is rapidly and widely distributed to all body
tissues and fluids, including the cerebrospinal fluid.
Metabolism of ethionamide is extensive, and several dihydropyridine
metabolites are produced. Less than 1%
of the drug is eliminated in the urine unchanged.
GI disturbances, including nausea, vomiting, and intense
gastric irritation, are frequent. In addition, ethionamide
may cause a wide range of neurological side
effects, such as confusion, peripheral neuropathy, psychosis,
and seizures. Neurological effects can be minimized
by pyridoxine supplementation. Other rare side
effects include gynecomastia, impotence, postural hypotension,
and menorrhagia.
Clinical Use
2-Ethylthioisonicotinamide (Trecator SC) occurs as a yellowcrystalline material that is sparingly soluble in water. Thisnicotinamide has weak bacteriostatic activity in vitro but, becauseof its lipid solubility, is effective in vivo. In contrast tothe isoniazid series, 2-substitution enhances activity in thethioisonicotinamide series.
Ethionamide is rapidly and completely absorbed followingoral administration. It is widely distributed throughoutthe body and extensively metabolized to predominantly inactiveforms that are excreted in the urine. Less than 1% ofthe parent drug appears in the urine.Ethionamide is considered a secondary drug for the treatmentof tuberculosis. It is used in the treatment of isoniazidresistanttuberculosis or when the patient is intolerant toisoniazid and other drugs. Because of its low potency, thehighest tolerated dose of ethionamide is usually recommended.Gastrointestinal intolerance is the most commonside effect associated with its use. Visual disturbances andhepatotoxicity have also been reported.
신진 대사
Ethionamide is orally active but is not well tolerated in a single large dose (>500 mg). The GI irritation can be reduced by administration with meals. Additional side effects may include central nervous system (CNS) effects, hepatitis, and hypersensitivities. Less than 1% of the drug is excreted in the free form, with the remainder of the drug appearing as one of six metabolites. Among the metabolites are ethionamide sulfoxide, 2-ethylisonicotinamide, and the N-methylated- 6-oxodihydropyridines.
Purification Methods
It crystallises from EtOH as lemon yellow needles. The hydrochloride crystallises from EtOH (+ few drops of HCl) as orange yellow needles with m 212-214o. [Kutscherowa et al. J Gen Chem USSR (English transl) 29 915 1959, Beilstein 22 III/IV 737.] It causes peripheral and occular neuropathy and is carcinogenic and teratogenic.
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