Isoniazid genetic factors

Hydralazine and isoniazid genetic factors in drug toxicity... 

The drug isoniazid causes two different toxic effects. What are they Are either of these effects due to a metabolite, and if so, which one Which genetic factor is important in the toxicity and why ... 

Genetic factors that influence enzyme levels account for some of these differences. Succinylcholine, for example, is metabolized only half as rapidly in persons with genetically determined defects in pseudocholinesterase as in persons with normally functioning pseudocholinesterase. Analogous pharmacogenetic differences are seen in the acetylation of isoniazid (Figure 4-5) and the hydroxylation of warfarin. The defect in slow acetylators (of isoniazid and similar amines) appears to be caused by the synthesis of less of the enzyme rather than of an abnormal form of it. Inherited as an autosomal recessive trait, the slow acetylator phenotype occurs in about 50% of blacks and... 

The acetylation of isoniazid and acetylhydrazine are both subject to genetic variability, so the production and detoxication pathways are both influenced by the acetylator phenotype. The hepatotoxicity of isoniazid is therefore dependent on a complex interrelationship between genetic factors and individual variation in the pharmacokinetics of isoniazid. Studies of the pharmacokinetics of acetylhydrazine in human subjects after a dose of isoniazid have revealed that although the peak plasma concentration of acetylhydrazine is higher in rapid acetylators, when the plasma concentration of acetylhydrazine is plotted against time, the area under the curve... 

Isoniazid causes peripheral neuropathy and liver damage (centrilobular necrosis). The liver damage is caused by a metabolite, acetylhydrazine whereas the peripheral neuropathy is caused by the parent drug interacting with pyridoxal phosphate and thereby interfering with the metabolism of vitamin B6. The genetic factor acetylator phenotype is important in both types of toxicity. Thus... 

A study found that aminosalicylic acid significantly increased the plasma levels of isoniazid at 4 and 6 hours after administration by 32% and 114%, respectively in fast acetylators of isoniazid, and by 21% and 39%, respectively in slow acetylators. The half-life of isoniazid was increased from 1.32 to 2.89 hours in fast acetylators and from 3.05 to 4.27 hours in slow acetylators (see Genetic factors , (p.4), for more information about acetylator status). The effects were probably due to the inhibition of isoniazid metabolism by aminosalicylic acid. There seem to be no reports of isoniazid toxicity arising from this interaction, but the manufacturers of isoniazid warn that adverse effects are more likely in the presence of aminosalicylic acid. ... 

Rifabutin 300 mg, given daily for 7 days to 6 healthy subjeets, had no significant effect on the pharmacokinetics of a single 300-mg dose of isoniazid or its metabolite acetylisoniazid. Two of the 6 subjects were rapid acetylators of isoniazid (see Genetic factors , (p.4), for more information about acetylator status). 

Human CYP2E1 is one of the most efficient P450s to catalyze the oxidation of acetaminophen to NAPQI (157-159). Ethanol and isoniazid cause a time-dependent inhibition and induction of acetaminophen oxidation to NAPQI in humans (160,161) that can decrease risk for hepatotoxicity over the interval of concurrent administration and increase risk for hepatotoxicity a few hours after removal of ethanol or isoniazid. The latter induction phase of CYP2E1 may, in part, be responsible for cases of acetaminophen hepatotoxicity associated with the use of ethanol (162-165) or isoniazid (166-168). However, the induction is modest (2- to 3-fold) therefore, other susceptibility factors, genetic and others such as decreased glutathione stores and nutritional status, are likely to play an important role in some individuals (169-174). 

Race and ethnicity may also be risk factors for ADRs. Prior personal or family history of ADRs may be predictive of future adverse reactions. Genetic polymorphisms for many metabolic reactions are described in Chapter 13 and have been well documented (45). Prescribing some medications without regard to genetic differences in metabolism can result in therapeutic failures or drug toxicity (45, 46). For example, differences in acetylator phenotype can alter the metabolism of some drugs and influence the risk of certain adverse reactions. Slow acetylators, for example, may be more likely than rapid acetylators to develop he pa to toxicity from isoniazid treatment. The biochemical basis for this difference is described in Chapter 16. 

Ethnic Differences. Ethnic differences are basically genetic, with different proportions of "normal" and slow metabolizers observed in different populations. However, the influence of environmental factors such as nutrition and lifestyle cannot be excluded. An early example was the phenotyping of slow and fast acetylators of isoniazid. Slow acetyla-tors (primarily caused by decreased activity of the NAT2 enzyme) exhibited a pronounced ethnic difference, e.g., 60% slow acetylators in Europe, —50% in Africa, —15% in China and Japan, and 5% in Canadian Inuit (Eskimo s) (117). It is now recognized that ethnicity and polymorphism are involved in a number of phase I and phase II enzymes, including CYP, FMO, methyltransferases, sulfotransferases, glucuronyltransferases, and acetylation. 

Susceptibility factors Genetic Hepatic metabolism of isoniazid involves acetylation to acetylisoniazid by 7V-acetyltransferase... 

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