Slow acetylation

About 30% of the patients on chronic procainamide dosing develop a systemic lupusfike syndrome consisting of arthralgia, myalgia, skin rash, and fever. Patients who are slow acetylator phenotypes may be prone to this condition. Some may exhibit pleuropneumonic involvement and hepatomegaly... 

JV-Acetyltransferases (NATs) catalyze the conjugation of an acetyl group from acetyl-CoA on to an amine, hydrazine or hydroxylamine moiety of an aromatic compound. NATs are involved in a variety of phase II-diug metabolizing processes. There are two isozymes NAT I and NAT II, which possess different substrate specificity profiles. The genes encoding NAT I and NAT II are both multi-allelic. Especially for NAT II, genetic polymoiphisms have been shown to result in different phenotypes (e.g., fast and slow acetylators). 

A/-acetyltransferase 2 Low activity in about 60% of Caucasian populations. High incidence of adverse events from the drug isoniazide in slow acetylators. 

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.

A study of 484 tuberculosis patients on isoniazid showed that the development of peripheral neuropathy in a subgroup of patients was due to inherited differences in the acetylation of this medication [4], Individuals could be divided into rapid or slow acetylators of isoniazid. Family studies showed that rapid or slow acetylation status was inherited, with rapid acetylation being dominant and slow acetylation recessive. Polyneuritis was found to occur in 4 out of 5 slow acetylators, while only 2 out of 10 rapid acetylators developed polyneuritis. The rapid acetylators also tolerated longer courses of the drug [4],... 

Finally, polymorphisms associated with arylamine N-acetyltransferase (NAT2) may result in slow acetylators. The slow-acetylator phenotype is present in 50-70% of the population in Western countries and is associated with several drug-induced side effects. The frequency of the slow-acetylator phenotype rises to 80% in Egyptian and certain Jewish populations however, the frequency drops to 10% or 20% among Japanese and Canadian Eskimos. 

The answer is b. (Hardman, pp 868 869.) Persons with low hepatic iY-acetyltransferase activity are known as slow acetylators. A major pathway of metabolism of procainamide, which is used to treat arrhythmias, is iV-acetylation. Slow acetylators receiving this drug are more susceptible than normal persons to side effects, because slow acetylators will have higher-than-normal blood levels of these drugs N-acetylprocainamide, the metabolite of procainamide, is also active. 

Hydralazine may cause a dose-related, reversible lupus-like syndrome, which is more common in slow acetylators. Lupus-like reactions can usually be avoided by using total daily doses of less than 200 mg. Other hydralazine side effects include dermatitis, drug fever, peripheral neuropathy, hepatitis, and vascular headaches. For these reasons, hydralazine has limited usefulness in the treatment of hypertension. However, it may be useful in patients with severe chronic kidney disease and in kidney failure. 

Therapy with INH results in a transient elevation in serum transaminases in 12% to 15% of patients and usually occurs within the first 8 to 12 weeks of therapy. Risk factors for hepatotoxicity include patient age, preexisting liver disease, and pregnancy or postpartum state. INH also may result in neurotoxicity, most frequently presenting as peripheral neuropathy or, in overdose, seizures, and coma. Patients with pyridoxine deficiency, such as alcoholics, children, and the malnourished, are at increased risk, as are patients who are slow acetylators of INH and those predisposed to neuropathy, such as those with diabetes. 

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) ... 

Consequence prolonged respiratory paralysis on exposure to the drug Suxamethonium (succinylcholine) for muscle relaxation for anesthesia Slow acetylator phenotype, due to mutations in liver N-acetylase transferase,... 

Some failures will be due to the presence of variants in drug handling. Patients who are rapid acetylators of isoniazid have a slower antituberculous response than slow acetylators (Evans and Clarke, 1961). Asthmatics who do not respond well to (32-agonist bronchodilators may have fewer functioning p2-adrenergic receptors (Drysdale et al., 2000). Variations in the synthesis or structure of the serotonin transporter protein, which is involved in selective reuptake of serotonin by presynaptic neurons, may explain why some patients with depressive disorders respond to selective serotonin reuptake inhibitors and others do not (Steimer et al., 2001). 

Carreon T, Ruder AM, Schulte PA, et al. NAT2 slow acetylation and bladder cancer in workers exposed to benzidine. Int J Cancer 2006 118(1) 161—168. 

Interesting information stems from studies of the hepatotoxic effect of the concomitant administration of rifampicin, another antituberculostatic drug (and a potent inducer of cytochrome P450) often used in combination with isoniazid. Rifampicin alone is not hepatotoxic but increases significantly the incidence of hepatitis in patients simultaneously dosed with isoniazid. In human volunteers (6 slow and 8 rapid acetylators), daily administration of rifampicin increased the release of hydrazine from isoniazid [180], In slow acetylators, the proportion of the dose metabolized to hydrazine increased... 

NAT2 enzyme, leading to slow acetylation (slow acetylator) of SSZ intermediates because of slow acetylation Fever, rash 53... 

There is no information regarding the metabolism of 3,3 -dichlorobenzidine in children. However, N-acetylation (as discussed above) in humans is likely done by one of two families of N-acetyltransferases. One of these families, NAT2, is developmentally regulated (Leeder and Kearns 1997). Some enzyme activity can be detected in the fetus by the end of the first trimester. Almost all infants exhibit the slow acetylator phenotype between birth and 2 months of age. The adult phenotype distribution is reached by the age of 4-6 months, whereas adult activity is found by approximately 1-3 years of age. Also, UDP-glucuronosyltransferase, responsible for the formation of glucuronide conjugates, seems to achieve adult activity by 6-18 months of age (Leeder and Kearns 1997). These data suggest that metabolism of 3,3 -dichlorobenzidine by infants will differ from that in adults in extent, rate, or both. 

Isoniazid is bactericidal against growing M. tuberculosis. Its mechanism of action remains unclear. (In the bacterium it is converted to isonicotinic acid, which is membrane impermeable, hence likely to accumulate intracellu-larly.) Isoniazid is rapidly absorbed after oral administration. In the liver, it is inactivated by acetylation, the rate of which is genetically controlled and shows a characteristic distribution in different ethnic groups (fast vs. slow acetylators). Notable adverse effects are peripheral neuropathy, optic neuritis preventable by administration of vitamin Be (pyridoxine) hepatitis, jaundice. 

Susceptibility to bladder cancer in humans has been linked to the slow acetylator phenotype of the polymorphic NAT2 AT-acetyltrans-ferase gene. In a study from China, a 25-fold increase in bladder cancer incidence and a 17-fold increase in bladder cancer mortality were determined in 1972 benzidine-exposed workers. In the Asian population the slow acetylator phenotype occurs significantly less often than in Caucasian populations, but an association between those who contracted bladder cancer and phenotype has yet to be determined for this group. Other, more recent data have suggested that the acetylation rate may not be an important risk factor for developing bladder cancer. ... 

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. 

Pharmacokinetics Hydralazine is rapidly absorbed after oral use. Half-life is 3 to 7 hours. Protein binding is 87%, and bioavailability is 30% to 50%. Plasma levels vary widely among individuals. Peak plasma concentrations occur 1 to 2 hours after ingestion duration of action is 6 to 12 hours. Hypotensive effects are seen 10 to 20 minutes after parenteral use and last 2 to 4 hours. Slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism it is excreted in the urine as active drug (12% to 14%) and metabolites. 

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. 

Blum, M. et al. (1991) Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proceedings of the National Academy of Sciences of the United States of America, 88 (12), 5237-5241. 

It required the growth of molecular genetics to probe the differences more intensely, and to discover in the 1980s and early 1990s that the gene coding for one of the two NAT (NAT I and NAT II) enzymes could exist in various forms, and that each form gave rise to a modified form of the enzyme which conferred properties of rapid or slow acetylation. The... 

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