Variability in the Formation of the Toxic Metabolite

For many forms of idiosyncratic drug toxicity, the adverse reaction is thought to be caused not by the parent drugs but by its toxic or chemically reactive metabolite, which can be formed through metabolism in the body, a process termed bioactivation. Such toxic metabolites can be readily detoxified in the majority of individuals, a process termed bioinacti-vation. However, if there is an imbalance between bioactivation and bioinactivation, which may in some cases be genetically determined, it can lead to binding of the toxic metabolites to essential proteins in the body leading to various forms of toxicity, including carcinogenicity, teratogenicity, necrosis, and hypersensitivity (10,73,74).

One of the best examples of drugs causing ADRs through this mechanism is sulfamethoxazole (SMX), which is given in combination with trimethoprim. It is used in a variety of infections, including urinary tract infections, and in immunosuppressed patients for the treatment of pneumocystis pneumonia (10,74,75). SMX undergoes extensive metabolism in vivo, the main routes of metabolism being N-acetylation, glucuronidation, N-hydroxylation, and 5-hydroxylation. Although the formation of the hydroxylamine and subsequent oxidation to the nitroso metabolite represents a minor metabolic pathway (catalyzed by CYP2C9), it has been implicated in pathogenesis of SMX hypersensitivity (76-78). It has been also shown in HIV-negative individuals that slow acety-lator phenotype is a risk factor for the development for hypersensitivity (76), the implication being that reduced N-acetylation allows a greater proportion of the drug to undergo metabolism via the toxication pathway, that is, through the formation of the hydroxylamine. Although this has not been shown in practice, it is a reasonable hypothesis because measurable quantities of the hydroxylamine in urine may not accurately reflect the total intracellular formation of the toxic metabolite. Interestingly, the frequency of SMX hypersensitivity is 10 to 30 times more common in HIV-positive patients; this seems to be a reflection of a disease-mediated change in the balance between these competing pathways, because it has been shown that neither slow acetylator genotype nor phenotype seems to predispose to SMX hypersensitivity (79-81).

Cure Your Yeast Infection For Good

Cure Your Yeast Infection For Good

The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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