Isoniazid pharmacogenetics

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... 

One of the first pharmacogenetic traits to be recognized more than 50 years ago was the slow acetylation of the antituberculosis drug isoniazid now known as the polymorphism of /V-acety11ranslerasc 2 (NAT2) and inherited as an autosomal recessive trait (reviewed in Refs. 11 and 12). 

Ohno M, Kubota R, Yasunaga M, Yokota S, Azuma J. Population pharmacokinetics and pharmacogenetics trial of isoniazid. Abstract PO-338, Clin and Exp Pharmacol and Physiol 2004 31 (suppl.), A138. 

The distribution is clearly bimodal (which means, it has two separate peaks). People with a plasma level of more than 2.5 mg/1 are deemed slow acetylators . This is actually a genetic trait that follows Mendelian inheritance, and it is obviously important for the individual adjustment of isoniazid dosage. It is the classical but by no means single example of genetic variation in drug metabolism. The study of phenomena of this type is called pharmacogenetics , and there actually is a scientific journal of that name. 

Other such enzyme deficiencies have been revealed through an individual s adverse reaction to drugs. More than 90% of Orientals are genetically rapid N-acetylators of isoniazid (6.12), whereas only 40% of black or white citizens of the United States showed this trait (Kalow, 1962). Rapid acetylators produce acetylhydrazine, which can cause liver damage. The same inheritance controls the acetylation (deactivation) of the sulphonamide antibacterials. The rise of intraocular pressure when glucocorticoids are placed in the eye is another pharmacogenetic effect. Low and high responses are shown by 66% and 5%, respectively, of a sample white population. 

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