Page 44 Complete Your CE Test Online - Click Here Drug interactions and effects in cancer treatment CYP 450 enzymes: A clinically important system As mentioned in the “Pre-treatment Assessment” section, most health professionals have heard of the CYP 450 drug interaction issue but many are not sure how it works. CYP 450 enzymes are mostly produced in the liver, but the gut produces them too. About ten of these enzymes can affect drugs in a significant way. These enzymes help to metabolize many drugs so that they can be inactivated and excreted [83]. It is important to know that, not only do the enzymes affect certain drugs, but there are some drugs that can affect the production of the enzymes. This means that one drug can indirectly affect another in significant ways. A drug that requires a certain enzyme to be metabolized is called a substrate of that enzyme. For example, alprazolam (Xanax) is a substrate of enzyme CYP 3A4, which is required to metabolize it. The half-life of this drug is usually about 11 hours (but can vary between six and 27 hours) [219]. This is typically fairly constant in each person, all other things being equal. However, if a person is taking an inducer of CYP 3A4, the alprazolam could leave the body very quickly. If the person is taking an inhibitor of CYP 3A4, the alprazolam blood level could climb much higher and last much longer in the body. Grapefruit and starfruit also act as 3A4 inhibitors, which means that patients taking alprazolam can intensify and extend the activity of this benzodiazepine if they drink grapefruit juice. While this may be a problem, it can be a more severe issue if they are taking a 3A4 substrate such as vincristine or imatinib (Gleevec), which might result in more unpredictable and severe toxicities. The most important of these enzymes are [230]: ● ● CYP 1A2. ● ● CYP 2B6. ● ● CYP 2C8. ● ● CYP 2C9. ● ● CYP 2C19. ● ● CYP 2D6. ● ● CYP 2E1. ● ● CYP 3A4,5,7 (these are typically grouped since they are related and on the same gene; sometimes the whole group is often called simply CYP 3A or the CYP 3A family). 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 (i.e. have their production increased) by certain drugs. To make things more confusing, some people have genetic mutations which cause them to produce more or less 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 [92]. Anti-cancer 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 [204]. On the other hand, an expert pharmacology website from Indiana University does not list these effects as clinically significant [92]. Interestingly, both of these statements can be true, since 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 due to magnitude of effect and other variables [203,204,205,206]. 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 due to CYP 450 enzymes [92]: ● ● 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, respectively. 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 (i.e. a particular drug) for cleanup. Normally, the water (i.e. 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 (i.e. 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) s/he 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 above 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 which can also prolong the interval [204]. According to the CredibleMeds website, the following drugs are potential causes of Torsades de Pointes (TdP) in those with other risk factors for TdP such as [78]: ● ● Congenital prolonged QT interval. ● ● Congestive heart failure. ● ● Bradycardia. ● ● Low potassium or magnesium. ● ● Use of other drugs that also prolong QT interval.