Page 25 Complete Your CE Test Online - Click Here Each of these enzymes has drugs that require that particular enzyme to be metabolized (they are substrates of that enzyme) and other drugs that inhibit that enzyme. Most of the enzymes can also be induced (have their production increased) by certain drugs. To make things more confusing, some people have genetic mutations that cause them to produce more or fewer of these enzymes. Those people do not have to take the inhibitor drug or the inducer drug to get an unexpected response to the substrate. The CYP 3A4,5,7 (usually called just group CYP 3A) affects a number of drugs used in cancer treatment. Some antidepressants, a couple of important nausea medicines, and tamoxifen are in the CYP 2D6 substrate column. Some common nonsteroidal anti-inflammatory drugs are CYP 2C9 substrates, along with warfarin and a couple of anticonvulsant drugs that have a number of off-label uses. There is no problem as long as the person produces the normal amount of the enzyme needed to metabolize the drugs and is not taking a CYP 2C9 enzyme inhibitor or inducer. Anticancer drugs, antiemetic drugs, and CYP enzyme interactions Some of the antiemetic drugs affect or are affected by other drugs via the CYP 450 enzyme system. The NCCN warns, for example, that aprepitant is a substrate of CYP 3A and induces CYP 2C9, although the effect is more pronounced with oral drugs than IV ones. On the other hand, an expert pharmacology website from Indiana University does not list these effects as clinically significant. Interestingly, both of these statements can be true because some substrates have other routes of excretion besides the one enzyme. And in vitro measurements of CYP enzyme induction or inhibition do not always predict major problems in vivo because of magnitude of effect and other variables. The Indiana University pharmacology expert table of clinically significant issues with drugs commonly used in cancer treatment and nausea and vomiting (N&V) management identifies these possible interactions because of CYP 450 enzymes. N&V drugs that are affected by the CYP enzyme system ● ● Olanzapine is a 1A2 enzyme substrate. ● ● Haloperidol is a 3A family enzyme substrate. ● ● Alprazolam is a 3A family enzyme substrate. Cancer treatment drugs that are affected by the CYP enzyme system ● ● Cyclophosphamide is a substrate of 2C19 and 2B6 enzymes. ● ● Ifosfamide is a 2B6 enzyme substrate. ● ● Paclitaxel is a 2C8 enzyme substrate. ● ● Vincristine is a 3A family enzyme substrate. When any of these drugs are given with other medicines that can inhibit or induce these particular enzymes, the drugs can have their excretion delayed or hastened. It is a good idea to check new drug information regularly. Drugs that speed up the production of a certain CYP enzyme are called inducers of that enzyme. They speed up the metabolism of the enzyme substrate drugs. To compare this system to something simpler, think of a substrate drug as something that is dumped in a certain shower stall (a particular drug) for cleanup. Normally, the water (the enzyme) comes from the shower head and washes it away at a standard pace. But an inhibitor can diminish the water flow so that it takes longer to wash out the substrate drug. A potent inhibitor can slow the shower down to a trickle leaving the substrate drug around for a very long time. On the other hand, an enzyme inducer speeds ups the water flow for that stall (enzyme system) and washes out the substrate drug very quickly. Suddenly, a person is getting much less of the drug because it is disappearing so fast. If the substrate is the kind of drug with noticeable therapeutic effects, the patient might report that it is not working well anymore. Someone taking imatinib will have the drug “washed out” by the enzymes induced by the phenytoin (inducer) she is also taking. Although the person is not likely to notice the difference in this case, it may affect treatment adversely by reducing the effectiveness of the imatinib. People who are genetically deficient in one or more of these enzymes may metabolize drugs differently even without a drug to cause an interaction. In the earlier analogy, the patient is missing the shower stall, but an enzyme-deficient patient can get little or no effect from a prodrug that requires enzyme activity to be metabolized to its active form, such as tamoxifen or codeine. Torsades de Pointes (prolonged QT interval and cardiac arrhythmias) The NCCN guidelines mention concerns about the abilities of certain antiemetic drugs to prolong the QT interval, which can be dangerous, especially to people with congenital QT prolongation or those taking other drugs that can also prolong the interval. According to the CredibleMeds website, the following drugs are potential causes of torsades de pointes (TdP) in those with other risk factors for TdP, including the following: ● ● Congenital prolonged QT interval. ● ● Congestive heart failure. ● ● Bradycardia. ● ● Low potassium or magnesium. ● ● Use of other drugs that also prolong QT interval. With any of the earlier mentioned risk factors, ondansetron, droperidol, and oxaliplatin are typically contraindicated. In treating cancer and N&V related to cancer drugs, there are a number of other medications that may affect QT interval enough to cause TdP or other arrhythmias in the presence of the risk factors for TdP. As noted earlier, these drugs are not categorically contraindicated as of early 2016, but use caution with the following. Antiemetic drugs ● ● Granisetron. ● ● Olanzapine. ● ● Promethazine. Cancer treatment drugs ● ● Arsenic trioxide. ● ● Bortezomib. ● ● Bosutinib. ● ● Ceritinib. ● ● Crizotinib. ● ● Dabrafenib. ● ● Dasatinib. ● ● Degarelix. ● ● Eribulin. ● ● Lapatinib. ● ● Lenvatinib. ● ● Leuprolide. ● ● Nilotinib. ● ● Osimertinib. ● ● Panobinostat. ● ● Pazopanib. ● ● Sorafenib. ● ● Sunitinib. ● ● Tamoxifen. ● ● Toremifene. ● ● Vandetanib. ● ● Vemurafenib. ● ● Vorinostat. It is important to continue to follow up on new drug additions to this list as new research is published. And, of course, new drugs come out all the time that may add to this list as well. Nursing consideration: Avoiding drug combinations that interact via the CYP enzyme system can maintain effectiveness of drug treatments and reduce the incidence of drug toxicity events. Inherited genetic mutations can affect response to drug treatment Germline (inherited) mutations can also affect responses to treatment. For example, women who were born with CYP 2D6 mutations do not produce enough of the enzyme that metabolizes certain drugs (e.g., CYP 2D6 substrates) (see “Drug interactions” for more detail). Tamoxifen, which is a commonly used breast cancer treatment that greatly reduces recurrence in women with estrogen receptor-positive breast cancer, must be metabolized by the CYP 2D6 enzyme to its active form, endoxifen. Some studies suggest that women with a germline genetic mutation