Metronidazole, oxidation

Leite AZ, Sipahi AM, Damiao AO, Coelho AM, Garcez AT, Machado MC, Buchpiguel CA, Lopasso FP, Lordello ML, Agostinho CL, Laudanna AA Protective effect of metronidazole on uncoupling mitochondrial oxidative phosphorylation induced by NSAID A new mechanism. Gut 2001 48 163-167. 

Metronidazole is a nitro-imidazole. It is a mixed amoebicide, i.e. it acts at all sites of infection. It has to be activated in the parasite. By reduction in the amoeba of its nitro group reactive intermediates are formed, resulting in oxidative damage and ultimately cell kill. It is effective against many parasitic intestinal and tissue infections such as trichomoniasis, giardiasis and amoebiasis. It is the drug of choice for amoebic dysentery and amoebic liver abscess. 

Absorption from the intestinal tract is usually good. Food delays but does not reduce absorption. The drug is distributed in body fluids and has a half-Ufe of about 8 hours. High levels are found in plasma and cerebrospinal fluid (CSF). Less than 20% binds to plasma proteins. Metronidazole is metabolized by oxidation and glucuronide formation in the liver and is primarily... 

Oxidation of acetaldehyde is inhibited by disulfiram, a drug that has been used to deter drinking by alcohol-dependent patients undergoing treatment. When ethanol is consumed in the presence of disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache. Several other drugs (eg, metronidazole, cefotetan, trimethoprim) inhibit ALDH and can cause a disulfiram-like reaction if combined with ethanol. 

The drug disulflram (Antabuse) is used in the treatment of chronic alcoholism, producing an acute sensitivity to alcohol. It inhibits the oxidation of acetaldehyde to acetic acid. Metronidazole produces a similar effect, which is why it should never be taken with alcohol. 

For. some nitro xenobiotics. biorcduction appears to be a minor metabolic pathway in vivo, because of competing oxidative and conjugative reactions. Under artificial anaerobic in viux) incubation conditions, however, these same nitro xenobiotics are enzymatically reduced rapidly. For example, most of the urinary metabolites of metronidazole found in humans are either oxidation or conjugation products. Reduced metabolites of metronidazole have not been detected. " When incubated anaerobically with guinea pig liver preparations, however, metronidazole undergoes considerable nitro reduction. ""... 

Inhibition of the enzyme has been shown with pentamidine and other aminoguanidine compounds -specifically aminoguanidine (pimagedine), some amiloride analogues, the alkaloid nazlinin and some derivatives, and metronidazole. Of these, aminoguanidine has mostly been used as a pharmacological tool in the past, but interpretation of findings is complicated by the recent demonstration that it is a potent nitric oxide synthase inhibitor. 

Certain drugs inhibit non-microsomal metabolic pathways. Metronidazole, like disulfiram, inhibits aldehyde dehydrogenase, the enzyme that normally oxidizes acetaldehyde to acetic acid in the metabolic pathway for ethanol. Allopurinol inhibits xanthine oxidase, the enzyme that catalyses the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Because azathioprine and 6-mercaptopurine are metabolized by xanthine oxidase, the dosage of these drugs (synthetic xanthine analogues), when used concomitantly with... 

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