Individual Variation in Drug Responses

Published on 08/04/2017 by admin

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Last modified 08/04/2017

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], a drug used to prevent breast cancer recurrence. Here’s how. To work, tamoxifen must first be converted to its active form—endoxifen—by CYP2D6. Women with an inherited deficiency in the CYP2D6 gene cannot activate the drug well, so they get minimal benefit from treatment. In one study, the cancer recurrence rate in these poor metabolizers was 9.5 times higher than in good metabolizers. Who are the poor metabolizers? Between 8% and 10% of women of European ancestry have gene variants that prevent them from metabolizing tamoxifen to endoxifen. At this time, the FDA neither requires nor recommends testing for variants in the CYP2D6 gene. However, a test kit is available.

Variants of the gene that codes for CYP2C19 can greatly reduce the benefits of clopidogrel [Plavix], a drug that prevents platelet aggregation. Like tamoxifen, clopidogrel is a prodrug that must undergo conversion to an active form. With clopidogrel, the conversion is catalyzed by CYP2C19. Unfortunately, about 25% of patients produce a variant form of the enzyme—CYP2C19*2. As a result, these people experience a weak antiplatelet response, which places them at increased risk for stroke, myocardial infarction, and other events. People with this genetic variation should use a different antiplatelet drug.

Among Americans of European heritage, about 52% metabolize isoniazid (a drug for tuberculosis) slowly and 48% metabolize it rapidly. Why? Because, owing to genetic differences, these people produce two different forms of N-acetyltransferase-2, the enzyme that metabolizes isoniazid. If dosage is not adjusted for these differences, the rapid metabolizers may experience treatment failure and the slow metabolizers may experience toxicity.

About 1 in 14 people of European heritage have a form of CYP2D6 that is unable to convert codeine into morphine, the active form of codeine. As a result, codeine cannot relieve pain in these people.

The following examples show how a genetically determined variation in drug metabolism can increase drug toxicity.

Variants in the gene that codes for CYP2C9 can increase the risk for toxicity (bleeding) from warfarin [Coumadin], an anticoagulant with a narrow TI. Bleeding occurs because (1) warfarin is inactivated by CYP2D9 and (2) patients with altered CYP2D9 genes produce a form of the enzyme that metabolizes warfarin slowly, allowing it to accumulate to dangerous levels. To reduce bleeding risk, the FDA now recommends that patients be tested for variants of the CYP2C9 gene. It should be noted, however, that in this case outcomes using expensive genetic tests are no better than outcomes using cheaper traditional tests, which directly measure the effect of warfarin on coagulation.

Variants in the gene that codes for thiopurine methyltransferase (TPMT) can reduce TPMT activity and can thereby delay the metabolic inactivation of two thiopurine anticancer drugs: thioguanine [generic only] and mercaptopurine [Purinethol]. As a result, in patients with inherited TPMT deficiency, standard doses of thiopurine or mercaptopurine can accumulate to high levels, posing a risk for potentially fatal bone marrow damage. To reduce risk, the FDA recommends testing for TPMT variants before using either drug. Patients who are found to be TPMT deficient should be given these drugs in reduced dosage.

In the United States, about 1% of the population produces a form of dihydropyrimidine dehydrogenase that does a poor job of metabolizing fluorouracil, a drug used to treat cancer. Several people with this inherited difference, while receiving standard doses of fluorouracil, have died from central nervous system injury owing to accumulation of the drug to toxic levels.

Genetic Variants That Alter Drug Targets

Genetic variations can alter the structure of drug receptors and other target molecules and can thereby influence drug responses. These variants have been documented in normal cells and in cancer cells and viruses.

Genetic variants that affect drug targets on normal cells are illustrated by these two examples.

Variants in the genes that code for the beta1-adrenergic receptor (ADRB1) produce receptors that are hyperresponsive to activation, which can be a mixed blessing. The bad news is that, in people with hypertension, activation of these receptors may produce an exaggerated increase in blood pressure. The good news is that, in people with hypertension, blockade of these receptors will therefore produce an exaggerated decrease in blood pressure. Population studies indicate that variant ADRB1 receptors occur more often in people of European ancestry than in people of African ancestry, which may explain why beta blockers work better, on average, against hypertension in people with light skin than in people with dark skin.

The anticoagulant warfarin works by inhibiting vitamin K epoxide reductase complex 1 (VKORC1). Variant genes that code for VKORC1 produce a form of the enzyme that can be easily inhibited, and hence anticoagulation can be achieved with low warfarin doses. If normal doses are given, anticoagulation will be excessive, and bleeding could result. To reduce risk, the FDA recommends testing for variants in the VKORC1 gene before warfarin is used.

Genetic variants that affect drug targets on cancer cells and viruses are illustrated by these three examples.

Trastuzumab [Herceptin], used for breast cancer, only works against tumors that overexpress human epidermal growth factor receptor type 2 (HER2). The HER2 protein, which serves as a receptor for hormones that stimulate tumor growth, is overexpressed in about 25% of breast cancer patients. Overexpression of HER2 is associated with a poor prognosis but also predicts a better response to trastuzumab. Accordingly, the FDA requires a positive test result for HER2 overexpression before trastuzumab is used.

Cetuximab [Erbitux], used mainly for metastatic colorectal cancer, only works against tumors that express the epidermal growth factor receptor (EGFR). All other tumors are unresponsive. Accordingly, the FDA requires evidence of EGFR expression if the drug is to be used.

Maraviroc [Selzentry], a drug for HIV infection, works by binding with a viral surface protein known as chemokine receptor 5 (CCR5), which certain strains of HIV require for entry into immune cells. HIV strains that use CCR5 are known as being CCR5 tropic. If maraviroc is to be of benefit, patients must be infected with one of these strains. Accordingly, before maraviroc is used, the FDA requires that testing be done to confirm that the infecting strain is indeed CCR5 tropic.

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