Module 7 Flashcards
What appear to be the most important genetic polymorphisms in drug metabolizing enzymes and provide an example of an important clinical consequence of each?
○ CYP2D6 activity is impaired in ~7% of Caucasians and African Americans, but less in Asian populations. This deficiency leads to decreased response to codeine and tamoxifen, both of which are prodrugs, i.e. they must be metabolized to their active form. CYP2D6 is also involved in the clearance of tricyclic antidepressants and venlafaxine, and poor metabolizers are at increased risk of adverse effects.
○ CYP2C19 activity is low in about 5% of Caucasians and 20% of Asians. It is involved in the metabolism of about 10 – 15% of current drugs. Clopidogrel and omeprazole are two important examples. In the case of clopidogrel CYP2C19 is responsible for converting the drug to its active form, and therefore poor metabolizers have decreased efficacy. In contrast, in the case of omeprazole, CYP2C19 is involved in clearance of the drug, and rapid metabolizers have decreased efficacy.
○ CYP2C9 is polymorphic with more than 50 single nucleotide polymorphisms (SNPs) known. Two important substrates are warfarin and phenytoin. In both cases the drug has a narrow therapeutic range, and CYP2C9 is a major enzyme involved in clearance. Therefore, slow metabolizers are more likely to have toxic levels of the drug unless the dose is reduced. It is involved in the metabolism of many other drugs, especially acidic drugs such as NSAIDs. It also can oxidize several endogenous fatty acids to epoxides.
○ Glucuronyltransferase, specifically UGT1A1, is deficient in about 5% of individuals, who are said to have Gilbert’s syndrome. Such patients have a 70-80% reduction in activity of the enzyme, but without significant clinical consequences. UGT1A1 is involved in the metabolism of many drugs, but it is especially important for the clearance of the anticancer drug irinotecan. (Actually, irinotecan is a prodrug, and it is the active metabolite that is cleared by glucuronidation.) Therefore, patients with impaired UGT1A1 activity have an increased risk of toxicity when treated with irinotecan, especially GI toxicity.
○ Thiopurine methyltransferase is important for the clearance of 6-mercaptopurine and its prodrug, azathioprine. About 0.25% of individuals are homozygous for the deficient gene. Therefore patients with a deficiency in this enzyme are at markedly increased risk of toxicity when treated with these drugs, especially when given at high dose for the treatment of leukemia.
Why are most CNS active drugs metabolized by CYP2D6?
Most CNS active drugs have a positively-charged nitrogen. This includes opiates, amphetamine and analogs, antidepressants, and antipsychotics. Exceptions are most anticonvulsants, benzodiazepines, and cannabinoids. If you remember from PHM144, most substrates with high affinity for CYP2D6 are positively charged basic amines that interact with CYP2D6 through an ion pair with a negatively charged glutamic acid on the enzyme
Studies of genetic polymorphisms in drug metabolism are usually performed by genotyping rather than phenotyping patients. This is because to determine a phenotype it is necessary to give the patient a drug that is metabolized almost exclusively by the enzyme in question, and then taking blood samples, in some cases multiple samples, and then analyzing the samples with some analytical technique such as HPLC, which is not rapid or easily automated. However, there are disadvantages to this strategy; what are they?
The major problem is that not all of the genotypes and their effects on activity are known. For example there are more than 100 known variants and subvariants of the CYP2D6 gene. It is very difficult to predict the phenotype from the genotype, and not every genotype has been identified and characterized. In addition, there are environmental factors that influence phenotype including drug interactions that can lead to induction or inhibition of enzyme activity. However, CYP2D6 is not as easily inducible as most P450s, and for a long time was not believed to be inducible at all.
What polymorphism is associated with an increased risk of cigarette addiction and tobacco-induced lung cancer?
CYP2A6. CYP2A6 is involved in conversion of nicotine to a pharmacologically inactive metabolite. Therefore, patients with increased expression of this enzyme are likely to smoke more to maintain a “therapeutic” blood level of nicotine. Ultra-rapid metabolizers often get up in the middle of the night to smoke to avoid withdrawal symptoms. Rapid changes in the blood level of an addictive substance also makes quitting more difficult. For example, methadone, with a long half-life is not as addictive and is used to withdraw from opiates. Therefore, it is usually more difficult for a patient with high CYP2A6 activity to quit. In addition, CYP2A6 also metabolizes carcinogens such as nitrosamines into their active form; therefore, patients with high levels of CYP2A6 are not only likely to smoke more, but they are also likely to produce more active carcinogen from the cigarette smoke.
What tests for genetic polymorphisms of drug metabolizing enzymes are available on a routine basis?
it is possible to be genotyped for thiopurine methyl transferase (risk of 6-mercaptopurine and azathioprine toxicity), glucuronyl transferase (risk of irinotecan toxicity). CYP2C9/VKORC1 (warfarin dose prediction), CYP2C19 (clopidogrel efficacy), CYP2D6 (tamoxifen efficacy), DPYD (5-FU toxicity), and SLCO1B1/ABCG2 (statin toxicity and efficacy). However, even these tests are usually not routine and are only performed in specialized labs.
What test should be performed before starting a patient on abacavir?
Abacavir can cause a severe idiosyncratic immune-mediated generalized adverse reaction in patients who carry the HLA-B*57:01 gene. If a patient carries this gene and receives abacavir there is more than a 50% chance they will have a severe reaction, and if they do not carry this gene the risk approaches zero
What test may be indicated before starting treatment with carbamazepine, who should be tested, and how well does it predict risk?
○ There is a much greater risk of Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN; TEN is a more severe form of SJS and caries a 30% mortality rate) in patients who carry the gene HLA-B1502 (a very high relative risk of about 2,500).
○ However, this gene is not associated with the adverse reaction called DRESS (drug reaction with rash, eosinophilia, and systemic symptoms) even though these two adverse reactions share many features. And even though the relative risk is extremely high, unlike the abacavir association with HLA-B5701, most patients who carry this gene will not develop SJS/TEN if treated with carbamazepine.
○ In addition, this gene is virtually absent except in Han Chinese; it is even absent in other East Asian populations such as Japanese and Koreans. In populations other than Han Chinese, the gene associated with increased risk of adverse reactions to carbamazepine is HLA-A*31:01. Even though most patients of Han Chinese decent will not develop SJS/TEN when treated with carbamazepine, the relative risk is so high and the rash so severe that it is recommended that patients of Chinese decent be genotyped before treatment with this drug.
What test should be performed before a patient is treated with dapsone? Is the same test required for patients before they are started on other arylamine drugs such as sulfonamide antibiotics or procainamide?
○ Dapsone is a primary aromatic amine that undergoes redox cycling with generation of reactive oxygen species. In patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, the red cells cannot make NADPH that is required to reduce the reactive oxygen species, and hemolytic anemia results. Therefore, patients, especially those of African American or Mediterranean decent, should be tested for G-6-PD deficiency before starting dapsone treatment. There are several other drugs such as primaquine that can cause hemolytic anemia in such patients. Although sulfamethoxazole and procainamide are also primary aromatic amines, the degree of redox cycling is much less. and these drugs do not cause hemolytic anemia at therapeutic doses, even in patients who are deficient in G-6-PD.
Why do patients with breast cancer who are treated with tamoxifen and are slow metabolizers of debrisoquine have a higher risk of tumor recurrence than those who have normal CYP2D6 levels? What implications does this have for drug interactions with tamoxifen?
○ Tamoxifen is a prodrug; the active agent is a phenolic metabolite formed by oxidation by CYP2D6. This is not surprising because it appears that all estrogens and SERMs (selective estrogen receptor modulators) are phenols. That means that a patient who lacks CYP2D6 will not benefit from tamoxifen treatment, although the clinical data are not as clear as might be expected. It also means that co-treatment with a drug that severely inhibits CYP2D6 will decrease the effect of tamoxifen. Therefore, if a patient is depressed because they have breast cancer and are prescribed an antidepressant such as fluoxetine, the risk of breast cancer recurrence will be increased.
It has been suggested that interindividual differences in drug response will lead to a different way of developing drugs and treating patients. How might this be accomplished?
This is referred to as personalized or individualized medicine. It is especially important in cancer treatment where different cancers of the same cell type respond differently. Given that cancer treatments are toxic, and the result of failure is death, choosing the right drug is crucial. It is now possible in some cases to genotype cancers and predict which treatment is likely to be successful. For example, trastuzumab (Herceptin) is only likely to have efficacy in breast cancer in which there is an overexpression of HER2. In this case it is the genotype of the cancer rather than the patient. Although individualized treatment is probably most important for cancer therapy, it can be very important for other types of treatments, and there are many links between specific gene polymorphisms and specific diseases and drug responses. The use of this strategy is likely to markedly increase in the future as a better understanding of the mechanisms that produce differences in drug response increases.
