Fast-acetylators

Due to the polymorphic acetylation of amonafide, a phenotyping procedure for amonafide acetylation using caffeine as a probe was evaluated in cancer patients. Slow and fast acetylators of both caffeine and amonafide were identified. Fast ace-... 

Fig. 14.9 Degree of leukopenia in cancer patients receiving amonafide. Incidence and degree of leukopenia was higher in fast acetylators compared to slow acetylators.

Hydralazine hydrochloride is rapidly metabolized and excreted. Experiments with carbon-14 labeled drug in humans indicated that less than 10 percent of the intact drug was excreted (36). Within 5 days after a dose, 83 to 89 percent was excreted in the urine and 9 to 12 percent in the feces. Of the material excreted in the urine, 96 percent was recovered in the first 24 hours. Individuals who are slow acetylators exhibit higher hydralazine blood levels than fast acetylators, for the same dose (37) ... 

The relation between the dosage, plasma concentration, and hypotensive action of hydrallazine has recently been examined (Zl). This drug, despite its many advantages as a hypotensive agent, fell from favor because of an unacceptably high incidence of severe side effects. Studies by Perry et al. (P8) have shown, however, that slow acetylators are more liable to develop the severe lupuslike syndrome associated with hydrallazine usage than fast acetylators. 

Mefabo//s/T - The observed plasma half-life for IV sulfasalazine is 7.6 hours. The primary route of metabolism of SP is via acetylation to form AcSP. The rate of metabolism of SP to AcSP is dependent on acetylator phenotype. In fast acetylators, the mean plasma half-life of SP is 10.4 hours, while in slow acetylators it is 14.8 hours. 

Fast/Slow acetylators The metabolism of SP to AcSP is mediated by polymorphic enzymes such that 2 distinct populations of slow and fast metabolizers exist. Approximately 60% of the white population can be classified as belonging to the slow acetylator phenotype. These subjects will display a prolonged plasma half-life for SP (14.8 vs 10.4 hours) and an accumulation of higher plasma levels of SP than fast acetylators. Subjects who were slow acetylators of SP showed a higher incidence of adverse reactions. 

Mefabo//sm - The half-life of INH is widely variable and dependent on acetylator status. Isoniazid is primarily acetylated by the liver this process is genetically controlled. Fast acetylators metabolize the drug about 5 to 6 times faster than slow acetylators. Several minor metabolites have been identified, one or more of which may be reactive (monoacetylhydrazine is suspected), and responsible for liver damage. The rate of acetylation does not significantly alter the effectiveness of INH. However, slow acetylation may lead to higher blood levels of the drug, and thus to an increase in toxic reactions. 

Although the half-life of an MAOI is short (hours), the half-life of MAO inhibition is about 2 weeks because it takes that long for the new enzyme to be synthesized. Some have speculated that phenelzine may be metabolized by acetylation and that there are two hereditary types (i.e., slow and fast acetylators), with slow acetylators presumably having a greater degree of MAO inhibition. There is limited support for the theory that slow acetylators have a better response, whereas other investigators find no difference (179). More importantly, there is no evidence that phenelzine is indeed acetylated. 

Sulfasalazine has a high incidence of adverse effects, most of which are attributable to systemic effects of the sulfapyridine molecule. Slow acetylators of sulfapyridine have more frequent and more severe adverse effects than fast acetylators. Up to 40% of patients cannot tolerate therapeutic doses of sulfasalazine. The most common problems are dose-related and include nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow suppression, and malaise. Hypersensitivity to sulfapyridine (or, rarely, 5-ASA) can result in fever, exfoliative dermatitis, pancreatitis, pneumonitis, hemolytic anemia, pericarditis, or hepatitis. Sulfasalazine has also been associated with oligospermia, which reverses upon discontinuation of the drug. Sulfasalazine impairs folate absorption and processing hence, dietary supplementation with 1 mg/d folic acid is recommended. 

An interesting example of racial differences in drug conversion is seen in the metabolism of the antitubercular, isoniazid. It is inactivated by an acetylation reaction. Slow acetylation leads to toxicity (lupus, drowsiness, nausea, cyanosis). Free isoniazid also inhibits the action of phenytoin (an anticonvulsive) and results in phenytoin toxicity. Normal acetylation has a half-life of 45-80 minutes while a "slow acetylator" shows a 140-200 min half-life. The U.S. population shows a 50/50 distribution of "slow" versus "fast" acetylators. 44-55% of American Causasians and blacks are "slow". 

With aromatic amines such as benzidine, 4-aminobiphenyl and 2-aminonaphthalene, which cause bladder cancer, epidemiological evidence suggests that those with the slow acetylator phenotype who have occupational exposure are more at risk. In contrast, with the heterocyclic amines produced in food by cooking, such as PhIP, which cause colon cancer, it seems from similar evidence that fast acetylators are more at risk. 

Importantly, these clinical studies were executed at a time when the molecular basis of the slow and fast acetylator phenotypes were not well understood. We now know that there are two isoforms of the /V-acetyltrans-ferase enzyme arising from two different genes, NAT1 and NAT2. Constitutive expression of NAT1 accounts for basal enzyme function, and functionally important polymorphisms in NAT2, are thought to contribute to variability in overall enzymatic activity and thus to define the slow- and fast-acetylators phenotypes (23,24). 

Orientals are fast acetylators. Separation of individuals into either rapid or slow acetylators is determined by variation at a single autosomal locus and constitutes one of the first discovered genetic polymorphisms of drug metabolism. In general, Eskimos are fast acetylators, while Jews and white North Africans are slow. The half-life of the acetylation reaction for isoniazid in fast acetylators is approximately 70 minutes, whereas in the slow acetylators this value is in excess of 3 hours. 

Isoniazid-induced hepatitis has an incidence estimated at 0.1%, but is higher in fast acetylators. 

Rifampicin is an enzyme inducer and can increase the incidence and severity of isoniazid-induced hepatitis. Carbamazepine is an enzyme induction agent and interacts with isoniazid, increasing its hepatotoxicity. Isoniazid toxicity is associated with fast acetylator genotype. Although his phenotype was unknown, the interaction with carbamazepine increases risk of this toxicity. 

Therefore the transformation of the 2-methoxynaphthalene acetic anhydride mixture over HBEA 15 can be proposed to occur through two main steps fast acetylation of 2-methoxynaphthalene preferentially into isomer I then slow isomerization and deacylation of this product (Figure 2),... 

PARACETAMOL ISONIAZID Risk of paracetamol toxicity at regular, therapeutic doses when co administered with isoniazid Uncertain it seems that formation of toxic metabolites is t in fast acetylators when isoniazid levels i (i.e. at the end of a dosing period) There have been cases of hepatic pathology regular paracetamol should be avoided in patients taking isoniazid... 

Therapeutic Concentration. There is considerable intersubject variation in plasma concentrations. The therapeutic effect has been correlated with plasma concentrations of about 4 to lOpg/ml of procainamide and 5 to 30pg/ml of combined procainamide and AA-acetylprocainamide. A -Acetylprocain-amide may accumulate during chronic administration in fast acetylators and in subjects with renal impairment. 

When the reaction with NPA was carried out at pH 8.0, the nitrophenol liberation due to the fast acetylation reaction was similar to those obtained in the experiments of pH 5.0. The catalysis of NPA hydrolysis subsequent to the initial fast reaction paralleled the activity towards ATEE. 

Acetylation is an important route of metabolism for many drugs that possess an amide (-NH ) group. Population studies have shown that most individuals are either rapid or slow acetylators but the proportion of each varies greatly between races. Some 90% of Japanese are rapid acetylators whereas in Western populations the proportion is 50% or less. Global trends are also recognised. Along the Pacific Asian littoral, the frequency of fast acetylators is highest near the Arctic (Inuit 95%) and falls towards the Equator. 

Drugs that have been shown to be subject to phar-macogenetic differences in biotransformation include debrisoquine, perhexiline, phenformin, mephenytoin, tolbutamide, dapsone, isoniazid and sulfadimidine. The latter three drugs are primarily biotransformed by Y-acetylation, a pathway for which about 50 /o of the United Kingdom population can be classified as slow acetylators and the rest as fast acetylators. 

The lupus-like syndrome (SED-9, 318) with hydralazine occurs particularly in slow acetylators (and only rarely in fast acetylators) and in patients with the HLA-DR4 antigen. Blood dyscrasias and necrotizing vasculitis are additional features. 

The lupus-like syndrome is more likely to occur in slow acetylators than in fast acetylators (50), and the rate of development of antinuclear antibody depends on acetyla-tor status (51). 

Side effects caused by isoniazid, rifampin, pyrazinamide, and ethambutol are common and can include hepatotoxic-ity, peripheral neuropathy, optic neuritis, and Gl side effects. All four agents can potentially be hepatotoxic, but this side effect is most frequently associated with isoniazid and rifampin. Peripheral neuropathy is most commonly associated with isoniazid, whereas optic neuritis is associated with ethambutol. The metabolism of isoniazid is genetically predetermined. Patients of Scandinavian, European, and African descent metabolize isoniazid slower (slow acetylators) and are therefore more predisposed to hepatotoxicity and peripheral neuropathy due to isoniazid. Fast acetylators include people of Asian or American Indian descent and are less predisposed to these adverse effects. 

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