Acetylator phenotype

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... 

Hildebrand, M. and Seifert, W., Determination of acetylator phenotype in Caucasians with caffeine. Journal of Clinical Pharmacology 37, 525-526, 1981. 

Carrillo, J. and Benitez, J., Caffeine metabolism in a healthy Spanish population N-Acetylator phenotype and oxidation pathways. Clinical Pharmacological Therapeutics 55, 293-304, 1994. 

Dose Individualization of Amonafide Based on N-Acetylator Phenotype... 

Ratain MJ, Mick R, Berezin F et al. Phase I study of amonafide dosing based on acetylator phenotype. Cancer Res 1993 53 2304-2308. 

Ratain MJ, Mick R, Janish L et al. Individualized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender. Pharmacogenetics 1996 6 93-101. 

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. 

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,... 

Frequency 45-65% of Caucasians and African Americans 10-15% of Asians Slow inactivation of drugs such as isoniazid (for tuberculosis), dapsone (for leprosy), and hydralazine (for high blood pressure), leading to toxicity from the drug at doses well tolerated in people with rapid acetylator phenotype Clinical consequences depend on the specific side effects of the drugs... 

Uetrecht, J.P. and Woosley, R.L., Acetylator phenotype and lupus erythematosus, Clin. Pharmacokinet., 6,118, 1981. 

Woosley, R.L. et al., Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome, New Engl. J. Med., 298, 1157, 1978. 

Acetylation mediated by NAT2 was one of the first metabolic pathways found to be polymorphic. The rapid and slow phenotypes are approximately equal in prevalence in North America, whereas about 90% of Orientals exhibit the rapid acetylator phenotype while the ratio is reversed in people of Middle Eastern decent. Although the NAT I gene is also polymorphic, the corresponding phenotype is not as clear. 

E. Musch, M. Eichelbaum, J. K. Wang, W. V. von Sassen, M. Castro-Parra, H. J. Deng-ler, Incidence of Hepatotoxic Side Effects during Antituberculosis Therapy (INH, RMP, EMB) in Relation to the Acetylator Phenotype , Klin. Wochenschr. 1982, 60, 513-519. 

P. Gurumurthy, M. S. Krishnamurthy, O. Nazereth, R. Parthasarathy, G. R. Sarma, P. R. Somasundaram, S. P. Tripathy, G. A. Ellard, Lack of Relationship between Hepatotoxicity and Acetylator Phenotype in Three Thousand South Indian Patients during Treatment with Isoniazid for Tuberculosis , Am. Rev. Respir. Dis. 1984, 129, 58-61. 

Das, K. M., Eastwood, M. A., McManus, J. P., and Sircus, W. (1973) Adverse reactions during salicylazosidfapyridine therapy and the relation with drug metabolism and acetylator phenotype. New England Journal of Medicine. 289, 491 95. 

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. 

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. ... 

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. 

Sulfasalazine is absorbed in the proximal intestine and is then excreted unchanged in the bile. In consequence most of orally administred sulfasalzine reaches the colon as such. It is then split by the intestinal flora into its components sulfapyridine, a sulfonamide antimicrobial agent, and 5-aminosalicylic acid (5-ASA). It has been proven that in inflammatory bowel disease 5-ASA is responsible for the beneficial effects while the sulpha component only contributes to the adverse reaction profile. Although some 5-ASA is absorbed and excreted in urine with a half-life of 0.5-1.5 hours, most is eliminated unchanged in the faeces. Sulfapyridine is to a major extend reabsorbed, metabolized in the liver and excreted in the urine with a half-life, depending on the acetylator phenotype, between 5 and 15 hours. 

The short-acting sulfonamides include sulfadimidine, sulfamerazine and sulfathiazole. Sulfadimidine, as the most important representative of this group, is relatively soluble and has therefore a lower risk of causing crystalluria while sulfamerazine and sulfathiazole are less soluble sulfonamides. Sulfadimidine has good oral absorption. It has an elimination half-life between 1.5 and 5 hours, depending on acetylator phenotype. 

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. 

Studies using liver from rapid and slow acetylator phenotype rabbits in vitro showed that there were indeed small differences in acetylation (2-2.5 x) for "monomorphic" substrates such as p-aminobenzoic acid, although much smaller than for "polymorphic" substrates (10-100x). 

There are examples where several genetic factors, including the acetylator phenotype, operate together. Hydralazine toxicity is one such example, which is discussed in detail in chapter 7. Another is the hemolytic anemia caused by the drug thiozalsulfone (Promizole), which occurs particularly in those individuals who are both glucose-6-phosphate dehydrogenase deficient and slow acetylators. Promizole is acetylated, and studies in rapid and slow acetylator mice confirmed that acetylation was a factor as well as an extent of hydroxylation. The latter may also be another factor in humans as is discussed below. 

Table 5.16 Acetylator Phenotype Distribution in Various Ethnic Groups...

Genetic factors are particularly important in humans and can influence the response to the compound or the disposition of the compound and hence its toxicity. Several genetic factors affecting metabolism are known in which a nonfunctional, less functional, or unstable form of the enzyme is produced in a particular phenotype, for example, acetylator phenotype... 

Ellard GA, Gammon PT, Titinen H. Determination of the acetylator phenotype using matrix isoniazid Tubercle. 1975 56 203-209. 

It is also clear that apart from exposure to carcinogens, other factors such as the genetic predisposition of the organism exposed may also be important. Thus, patients with the genetic disease xeroderma pigmentosum are more susceptible to skin cancer. It has already been mentioned that the incidence of bladder cancer is significantly higher in those individuals who have the slow acetylator phenotype. 

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