Info

Slow

Nausea/vomiting

[33]

Amonafide

Rapid

Leukopenia

[34,35]

Procainamide

Slow

Systemic lupus erythematosus

[36,37]

Phenelzine

Rapid

Decreased therapeutic effect

[38]

p-Phenylenediamine

Slow

Contact dermatitis

[39]

Source: Adapted from Ref. [3].

agents are now known to be polymorphically acetylated in humans. However, the incidence of failed or less effective clinical response as a consequence of acetylation polymorphism is uncommon. This is because most drugs that are metabolized by the NATs have a wide therapeutic window or because acetylation is a minor metabolic pathway. An exception is hydralazine. Early studies showed that the antihypertensive activity of hydralazine was less in rapid acetylators and that a 40% higher dose was necessary for a similar therapeutic effect compared with slow acetylators.[23] This difference appeared to be due to a change in the bioavailability of the drug, which decreased from 33% in slow acetylators to less than 10% in rapid acetylators.

A more common consequence of the polymorphic acetylation of therapeutic agents is an increase in the frequency and severity of side effects associated with either the rapid or slow phenotype (Table 1). These adverse effects often arise as the result of a shift in the metabolic pathways responsible for the activation and detoxification of the drug. This is best illustrated by the amine-containing sulfonamides, such as sulfamethoxa-zole, that undergo hydroxylation to a reactive N-hydroxy metabolite capable of covalently binding to macromole-cules and giving rise to idiosyncratic adverse reactions. These drugs can also be acetylated by NAT2 to non-reactive N-acetyl metabolites. In slow acetylators, a higher proportion of the drug is N-hydroxylated and, consequently, these individuals are at a greater risk of sul-fonamide-induced toxicity. However, the incidence of severe adverse side effects to sulfonamides is much less than the incidence of the slow acetylator phenotype suggesting that other factors predispose individuals to idiosyncratic adverse reactions.

Risk of developing side effects, such as neurotoxicity or hemolytic anemia, to dapsone therapy is very similar to that described for the sulfonamides. The most severe incidence of toxicity occurred in individuals with a slow acetylator phenotype who are rapid hydroxylators, which is consistent with the role each pathway has in the activation and detoxification of the drug.

While slow acetylators are at a greater risk of toxicity from sulfonamides and dapsone, other therapeutic agents exhibit increased incidence of adverse reactions in rapid acetylators. Amonafide is a novel arylamine that has previously been in clinical trials for the treatment of various cancers. It undergoes N-acetylation to an active metabolite that contributes to systemic toxicity. Several studies have shown that myelosuppression is greater in rapid acetylators (white blood cell nadirs of 500/p.L) than in slow acetylators (white blood cell nadirs of 3400/p.L) following a standard dose of 300 mg/m2 daily for 5 days.[35] This has led to different recommended doses for the two groups.[34]

Detoxification and Weight Loss

Detoxification and Weight Loss

Detoxification is something that is very important to the body, but it is something that isn't understood well. Centuries ago, health masters in the East understood the importance of balancing and detoxifying the body. It's something that Western medicine is only beginning to understand.

Get My Free Ebook


Post a comment