[...] awareness of these pharmacogenetic influences can serve as an ally in your treatment of patients, especially with such commonly prescribed drugs as rosuvastatin and warfarin. [...] while DNA testing may be useful for some patients, others will have genotypes that are rare or have not yet been discovered, so testing cannot yet be applied universally.
genomics0709.qxp 6/24/09 3:15 PM Page 61 GENOMICS IN PA PRACTICE L AW R E N C E C A R E Y, P h a r m D Pharmacogenetics: What PAs need to understand and why he field of pharmacogenetics of our pharmacologic dilemmas. A due to a lack (or variant form) of T changes on what seems to be a daily basis. The constant coming forward of groundbreaking few of the drugs metabolized by the CYP450 system are listed in Table 1. Transport proteins Other genetic some enzyme responsible for metab- olism of that particular agent. This can be seen in the metabolism of information underscores the need for influences exist. Drug-transport pro- 6-mercaptopurine, in which a lack practicing PAs to have a fundamental teins, such as P-glycoprotein, may also of thiopurine methyltransferase may understanding of basic pharmacoge- affect drug response. P-glycoprotein result in toxicity requiring significant netic concepts. These concepts are not is one of the most recognized drug- dose reductions. entirely new; the idea of a pharmaco- transport proteins to exhibit genetic Adverse impact PAs must under- genetic influence was first explained in polymorphism. In addition to acting stand the principles of pharmacogenetics the 1950s. However, with the advent as an efflux pump to get toxic sub- because of the possible adverse impact of newer drugs, as well as a better un- stances out of cells, P-glycoprotein genes can have on patients’ response derstanding of existing drugs, pharma- has a role in the distribution of che- to medication. When a drug “fails” or cogenetics takes on greater importance motherapeutic agents, digoxin, cy- causes significant toxicity, most unre- as clinicians realize the impact it can closporine, and protease inhibitors. sponsive patients (as well as the clini- have on patient care. P-glycoprotein can also affect drug cians treating them) assume that the Cytochrome P-450 system We must absorption via its presence in the GI drug, acting as an isolated entity, is re- start at the beginning. A large part of tract, hepatocytes, kidney, and blood- sponsible. In reality, this response may our current understanding of pharma- brain barrier. For instance, cellular be due to a patient-specific pharmacoge- cogenetics is centered on the cyto- overexpression of P-glycoprotein caus- netic issue rather than to the drug. chrome P-450 (CYP450) system, the es decreased absorption and increased The problems with impaired metab- major drug-metabolizing system of the efflux of certain therapeutic agents out olism are not limited to niche-area body. Genes responsible for encoding of cells, which may result in treatment drugs, such as chemotherapy agents; CYP enzymes are identified by the let- failure resulting from reduced activity we are seeing the results of impaired ters “CYP,” as are the enzymes them- of the drug. More important, underex- medication metabolism in the primary selves. CYPs are the major enzymes pression may cause significant toxicity care arena as well. Ethnicity has been involved in drug metabolism and bio- at normal doses; for example, over- shown to have a significant influence activation. They account for approxi- whelming toxicity that occurs with use on how certain medications are me- mately 75% of total drug metabolism of a chemotherapeutic agent may be tabolized. Certain ethnic groups have and are responsible
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