Pharmacogenomics is a rapidly growing area of knowledge regarding the genetic variations that influence drug metabolism and drug effects. Most of the research in this field to date has involved phase I or phase II drug metabolism and drug transporters. Application of genomic analysis of individual patients to selection of specific drugs and drug dosage (“precision” or “personalized” medicine) is progressing.
The inheritance of genetic information via the DNA double helix is now well understood. The decoding of the human genome and of many animal and plant genomes has opened a field of research into the molecular basis of variations between individuals and among populations. The identification of the specific genes (or groups of genes) that affect drug responses is still incomplete, but knowledge about a small number of the genes of pharmacologic significance has suggested the possibility that personalized medicine is possible and may become practical in the near future.
Personalized medicine denotes clinical treatment that takes into account the genetic factors that contribute to disease and the pharmacogenomic factors that influence the response to drug treatment in specific individuals. Intense academic and commercial research is currently directed at discovering these factors. Research is also directed at developing accurate and inexpensive tests for pharmacogenetic factors in individual patients.
As noted in Chapter 4, important genetic variations in drug metabolism exist among individuals. Furthermore, genetic diseases alter many functions that are drug targets. The identification of specific genes that control the expression of the molecules involved and the variants (polymorphisms) of those genes has become the subject of intense research over the last 20 years. At present, data are available regarding the variants of the genes for some phase I and phase II enzymes and some drug transporters. Examples of these genetic determinants of drug metabolism and transport are the subject of this chapter.
CYP2D6, CYP2C19, CYP3A4/5, and dihydropyrimidine dehydrogenase are among the drug-metabolizing enzymes most carefully studied to date (Table 5–1).
TABLE 5–1Polymorphisms associated with altered drug responses. ||Download (.pdf) TABLE 5–1 Polymorphisms associated with altered drug responses.
|Functional Element ||Alleles or SNPs of Major Importance ||Examples of Drugs Affected |
|Phase I enzyme || || |
|CYP2C9 ||*2, *3: decreased function ||Warfarin, phenytoin, antidiabetic sulfonylurea metabolism slowed, toxicity increased |
|CYP2C19 || |
*17: increased function,
*2, *3: decreased function
|Increased or decreased clopidogrel active metabolite |
|CYP2D6 || |
*1, *2: increased function
*3, *4, *5: decreased function
|Codeine converted to morphine. Increased function associated with increased toxicity; decreased function associated with decreased analgesia. Increased toxicity of many other drugs |
3A5 (SNPs more common in 3A5)
*1, *8, *11, *13, *16, *17: decreased function
*3, *5, *6, *7: decreased function
|Metabolism of some dihydropyridines, cyclosporine, tacrolimus reduced; increased toxicity |
|Dihydropyrimidine dehydrogenase (DPD) ||DPYD *2A,...|