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Genetic Mutations in Cytrochrome P 450 2D6

Ask the Expert from March 2014

Question: A patient recently found out that she has a genetic mutation, cytochrome P 450 (CYP450) 2D6, and that she is a poor metabolizer. One of her alleles is null, while the other works at a very low rate. I am not that familiar with these mutations, and I am hoping you may be able to give me some more information on what the mutation is? I am mostly concerned with what medications can my patient take, as well as what alternatives are available.

Answer: The majority of opioid medications are metabolized by one or more of the CYP450 isozymes.1 In terms of CYP 450-related drug metabolism, there are 9 CYP isoenzymes of known clinical importance and they are referred to as CYP-1A2, CYP-2B6, CYP-2C9, CYP-2C18, CYP-2C19, CYP-2D6, CYP-2E1, and CYP-3A4.2 Of those drugs that undergo liver metabolism, a specific CYP enzyme (or a combination of enzymes) is responsible for each drug’s metabolism. Pharmacogenomic testing can be used to assess the activity of CYP450 isozymes (3A4, 2C9, 2C19, 2D6) prior to administration of an agent to predict a patient’s response.3

A poor metabolizer of CYP2D6, like the patient described here, will not be able to metabolize certain opioids in the liver, resulting in an increase in the blood level of the parent drug and a decrease in its metabolites. These individuals have a tendency to become toxic on the “usual” doses of medications. Opioid drugs most affected by CYP2D6 include: codeine, hydrocodone, and tramadol. The following opioids are also affected by CYP2DC, but may provide some pain relief when given at higher dosage: oxycodone, meperidine, and methadone.

There is some danger if you attempt to take any of the opioid drugs noted above. Patients who are poor metabolizers can overdose or have a toxic reaction as the opioid can accumulate in the blood and interact with other drugs. This is particularly true for patients also prescribed a sedative, muscle relaxant, or antidepressant. The most hazardous class of sedatives includes benzodiazepines, of which the best known are diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan), and clonazepam (Klonopin).

Did you test for other cytochrome P450 defects? It is critical to know if the patient also has defects in the 2C9, 2C19, or 3A4 enzymes. If she has 2 or more defects, she may not be able to effectively take oral opioids as these enzymes are in the intestine and promote absorption into the blood, which is necessary for them to be effective.

Many patients with cytochrome P450 defects must resort to opioid drugs that do not utilize the cytochrome system for drug metabolism, but use an alternative system referred to as Phase-2 metabolism, or glucoronidation. There are
4 opioid drugs that do not use the cytochrome system: morphine, hydromorphone, oxymorphone, and tapentadol. Another option is to use an alternative route of administration, such as transdermal patch (ie, fentanyl and buprenorphine), which bypass the first pass (Phase One) effect and generate significantly fewer metabolites. Metabolite levels can rise, however, with long-term application of patches.

The major message about cytochrome P450 genetic testing is that patients who are not getting good pain relief should be tested.3 Remember, genetic testing need only be done once. With the test results in hand, a knowledgeable pain practitioner can select a pain reliever that is effective.

Forest Tennant, MD, DrPH

Last updated on: May 30, 2014
First published on: March 1, 2014