Toxic metabolite formation, prevention

Prevention of toxic metabolite formation. Antidotes in this class are most active when given shortly after ecposure to the toxicant and before agnifkant metabolic activation has occurr. ... 

An antibiotic drug that is itself nontoxic may have metabolites that are toxic, diminishing its usefulness. For example, imipenem is hydrolyzed by renal dipeptidase to a metabohte that is inactive against bacteria but is toxic to humans. Coadministration of cilastatin inhibits the renal dipeptidase, which both prevents the formation of the toxic metabolite and decreases imipenem clearance, prolonging the half-life of the drug. 

Answer You decide that a metabolite of imipenem is responsible for the sudden toxicity. You add a second drug, cilastatin, to the patient s regimen. Coadministration of cilastatin inhibits renal dipeptidase, the enzyme responsible for the metabolism of imipenem. This prevents the formation of the toxic metabolite and decreases the clearance of imipenem. The side effect disappears within 12 hours and the patient recovers from the infection. 

The widespread use of isoniazid prophylaxis for tuberculosis has focused attention on the liver injury caused by this drug. About 20% of patients treated with isoniazid will show elevated blood concentrations of liver enzymes and bilirubin that subside as treatment is continued (25). However/ clinical hepatitis develops in some patientS/ and these reactions can prove fatal. Current understanding of the mechanism of isoniazid-induced hepatotoxicity is based on the metabolic pathways shown in Figure 16.6 (26/ 27). It has been demonstrated in an animal model that hepatotoxicity is correlated with plasma concentrations of hydrazine but not of acetylhydrazine or isoniazid (28)/ and that pretreatment with an amidase inhibitor can prevent toxicity (27). However/ it is postulated that hydrazine is further metabolized to a chemically reactive he pa to toxin by the cytochrome P450 system/ and in vitro studies with hepatocytes have implicated CYP2E1 as the cytochrome P450 isoform responsible for cytotoxic metabolite formation (29). 

Treatment begins with supportive care, and enteric suction is useful only if recent ingestion or retained gastric methanol is suspected. To prevent formation of toxic metabolites, fomepizole (4-methyl pyrazole or 4-MP) or ethanol to inhibit ADH should be administered. Fomepizole is preferred over ethanol if available [93]. It is well tolerated and may improve initial visual defects [94]. Mild methanol poisoning with levels below 20 mg/ dL can likely be treated with fomepizole only and bicarbonate however a methanol elimination half-life of over 50 hours with fomepizole requires prolonged infusion and monitoring [95]. Folic or folinic acid should be administered to promote conversion of formate to water and carbon dioxide [96]. 

Treatment should include correction of metabolic acidosis, inhibition of ethylene glycol metabolism and if necessary, extracorporeal elimination of the parent alcohol and metabolites. Acidemia likely increases tissue penetration of toxic metabolites and hinders renal clearance. Although evidence is lacking, bicarbonate administration should be given to correct acidemia. Although more expensive, fomepizole is preferred to ethanol for ADH inhibition due to proven efficacy, predictable pharmacokinetics, and lack of adverse effects [105]. Inhibition of ADH with fomepizole prevents formation of toxic metabolites and renal injury, and improves add-base status [106]. Elimination half-life of ethylene glycol with fomepizole in patients with preserved renal function is approximately 20 hours [107]. Pyridoxine and thiamine should be administered to promote glyoxyhc add conversion less toxic metabolites than oxalate [108]. 

Genistein and daidzein directly affect testosterone metabolism, reducing the toxic metabolites of testosterone. Genistein, an isoflavone, also seems to slow or prevent the metastasis of invasive cancer cells. It is believed to work by preventing the formation of new blood vessels to cancerous tumors. Histoculture studies of genistein have shown that this phytochemical reduces the growth of prostatic cancer tissue. 

MPTP causes parkinson-like extrapjramidal dysfunction by destroying dopaminergic neurons in the nigrostriatal tract. This neurotoxic action requires the formation of toxic metabolites from the metabolism of MPTP by monoamine oxidase type B. Toxicity is prevented by selegiline, a selective inhibitor of MAO type B. MPTP is used as an experimental tool in animal models of parkinsonism. The answer is (E). 

Administer fomepizoie (see p 448) or ethanoi (p 444) to saturate the enzyme alcohol dehydrogenase and prevent the formation of methanol s toxic metabolites. Therapy is indicated in patients with the following ... 

The O2 molecule is essential to all aerobic forms of life, but many anaerobic organisms (e.g. anaerobic bacteria such as Clostridia spp.) are killed after only brief exposures to molecular O2. However, it is well established that even aerobic organisms, including man and other animals, show signs of oxygen toxicity when exposed to O2 tensions above those normally found in air (i.e. >21% O2). Such toxicity does not normally occur because aerobic cells possess protective enzymes that prevent either the formation or the accumulation of oxygen metabolites. It is only when these protective systems be-... 

Oxidation of phenols is one of the most important aspects of these compounds to the biologist. Oxidation of phenolic compounds can result in the browning of tissues. Well-known examples are the browning of lfuits after they have been cut. Oxidation can also result in the formation of metabolites that are toxic to animals and plants, and that can account for spoilage of foods in processing. On the other hand, toxic compounds formed from the oxidation of phenolics can inhibit pathogenic microorganisms. Certain phenols are used as retardants or antioxidants to prevent the oxidation of fatty acids. 

Methods of Reducing Toxic Effects. Due to formaldehyde s high water solubility and reactivity and the rapidity of cellular metabolism of formaldehyde to formate and CO2, toxic effects from formaldehyde are expected to be principally caused by fonnaldehyde itself (not metabolites) and to be restricted to portal-of-entry tissues, except at high exposure levels that exceed metabolic capacities of these tissues. Thus, following acute exposures to formaldehyde, treatments that dilute or remove non-absorbed or non-reacted formaldehyde from the site of exposure or that present alternative substrates for reaction (e.g., washing of the skin or eyes or dilution of ingested fonnaldehyde with milk or water) may prevent the occurrence of toxic effects if applied in a timely manner. Methods that may enhance the capacity of portal-of-entry tissues to metabolize fonnaldehyde may be expected to act against the toxic action of formaldehvde, but no such methods have been established. Tliere are no established treatment... 

There are several one-carbon derivatives of folate (of different redox states) that function as one-carbon carriers in different metabolic processes. In all of these reactions, the one-carbon moiety is carried in a covalent linkage to one or both of the nitrogen atoms at the 5- and 10-positions of the pteroic acid portion of tetrahydrofolate. Six known forms of carrier are shown in Figure 27-4. Folinic acid (N -formyl FH4), also called leucovorin or citrovorum factor, is chemically stable and is used clinically to prevent or reverse the toxic effect of folate antimetabolites, such as methotrexate and pyrimethamine. The formation and interconversion of some metabolites of... 

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