Pharmacogenomics
Predicting Which Drugs Will Work and Which Won't
Benefits of Pharmacogenomic Testing
As with other types of genetic testing, pharmacogenomic tests usually require only a small sample, such as blood or a scraping from inside the cheek. Results would let the physician predict whether someone will respond positively to drug therapy within hours rather than in the days or weeks it might take with the trial-and-error method and with substantially less risk to the patient. In the end, these tests may give doctors invaluable information about their patients not otherwise available to them.
Patient's Ability to Metabolize Drugs
Testing patients prior to initiating drug therapy to determine their ability to metabolize different classes of drugs is a key emerging area of investigation. Such metabolic information could prove useful to both the doctor and patient when choosing current and future drug therapies and drug doses.
There are a number of types of enzymes in the liver that metabolize medications. Genetic variations in these enzymes that affect metabolic rate are relatively common, but the prevalence of the variations differs significantly by ethnic background. Some of these enzymes include:
The Cytochrome P450 family: Some of the most studied enzymes are the members of the Cytochrome P450 (CYP) family of about 50 liver enzymes. These enzymes metabolize more than 30 classes of drugs, including antidepressants, antiepileptics and cardiovascular drugs. Patients can be separated into poor, normal and ultra-rapid metabolizers of drugs by the CYP enzymes. These classifications are due to variations in the associated CYP gene. When a poor metabolizer of a particular drug is given a standard dose of that drug, he will process the drug more slowly, resulting in increased levels of the drug in his bloodstream, the potential for side effects, and an increased risk of toxicity. For an ultra-rapid metabolizer, the same dose may be ineffective as the drug is processed too rapidly to have its full effect. Dosages of these drugs must be altered to accommodate the rate of metabolism. The CYP family is important as it affects the metabolism of a significant percentage of available drugs and because a significant proportion of the population are poor or ultra-rapid metabolizers.
N-acetyltransferase: This is a liver enzyme that activates some drugs and deactivates others. Some patients can acetylate (a type of metabolic change) drugs slowly while other patients acetylate drugs quickly. Those who are slow acetylators may experience toxicity when taking drugs such as procainamide, isoniazid, hydralazine, and sulfonamides. Those who are fast acetylators may not respond to isoniazid or hydralazine. About 40 to 70% of Caucasians and African-Americans are considered slow acetylators.
Thiopurine methyltransferase (TPMT): This enzyme metabolizes the immune suppressant azathioprine and other thiopurine medications such as 6-mercaptopurine and 6-thioguanine (used to treat children with acute lymphocytic leukemia and also used to treat autoimmune diseases). Each copy of the TPMT gene will produce some TPMT enzyme. This leads to three different groups of enzyme activity levels (low/low, low/high, and high/high or deficient, intermediate, and normal). About 1 in 300 Caucasians and African-Americans are TPMT- deficient. If these patients are given a standard drug dose, they may suffer severe hematopoietic (red blood cell producing) toxicity. Many are able to achieve the desired therapeutic effect from a dose that is one tenth of the “normal” dose.
UDP-glucuronosyltransferase: This enzyme is involved in the metabolism of the chemotherapy drug irinotecan, which is used in the treatment of metastatic colorectal cancer. Variations in the gene that code for this enzyme can influence the patient's ability to break down the major active metabolite. The inability to break the metabolite down can lead to increased levels of it in the blood and a higher risk of side effects, which include reduced white blood cell count and severe diarrhea.
Age-related Genetic Variations
Some researchers are looking at changes in genetic variation over time to help evaluate how age may affect genetic response to drug therapy.
