Drug toxicity, genetic factors

The metabolic and clinical condition of the patient also plays a role The individual with good kidney and liver function will respond quite differently to a drug than the patient who is not able to detoxify or excrete the compound. The user of laboratory data must be aware of the possible occurrence of drug-mediated enzyme induction, biological variations in the rate of clearance and storage in depot areas (B24), and the genetic factors that play a role in the toxicity of a drug (L2). 

There are many examples of human subjects showing idiosyncratic reactions to the pharmacological or toxicological actions of drugs. In some cases, the genetic basis of such reactions has been established, and these cases underline the need for an understanding and appreciation of genetic factors and their role in the causation of toxicity. 

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. 

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 ... 

The influence of genetic factors is readily apparent when comparing normal differences in drug toxicity within a species, between genders of the same species, as well as strain differences within the same species. In addition, there are also examples of drug toxicity related to abnormal genetic expression. We will consider significant aspects of both situations in this section. 

Hydralazine and isoniazid genetic factors in drug toxicity... 

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. 

Eichelbaum M, Kroemer H, Mikus G. Genetically determined differences in drug metabolism as a risk factor in drug toxicity. Toxicol Lett 1992 64/65 115-22. 

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