Cytochrome P450 Drug Interactions
Looking beyond the obvious takes time, energy, insight, and fortitude; yet this is what we are called to do. We are nursestireless care providers. Yet, when the subject of the liver's enzyme system, also called the cytochrome P450 system, is discussed, we feel the urge to run the other way...or better yet, to just ignore the conversation. Yet, can we do this as the tireless care provider? The answer to this question is clear and simple: no, we cannot. This is because numerous medications, nutrients, and herbal therapies are metabolized through the cytochrome P450 (CYP450) enzyme system. This system can be inhibited or induced by drugs, and once altered can be clinically significant in the development of drug-drug interactions that may cause unanticipated adverse reactions or therapeutic failures. This article will review the basic concepts of the CYP450 system and relate these concepts to clinically significant altered responses.
The CYP450 enzymes are essential for the production of numerous agents including cholesterol and steroids. Additionally, these enzymes are necessary for the detoxification of foreign chemicals and the metabolism of drugs. CYP450 enzymes are so named because they are bound to membranes within a cell (cyto) and contain a heme pigment (chrome and P) that absorbs light at a wavelength of 450 nm when exposed to carbon monoxide. There are more than 50 CYP450 enzymes, but the CYP1A2, CYP2C19, CYP2D6, CYP1A2, CYP3A4, and CYP3A5 enzymes are responsible for metabolizing 45% of drug metabolism. The CYP2D6 (2030%), the CYP2C9 (10%) and the CYP2E1 and CYP1A2 (5%) complete this enzyme system.
Drugs that cause CYP450 drug interactions are referred to as either inhibitors or inducers. An inducing agent can increase the rate of another drug's metabolism by as much as two- to threefold which develops over a period of a week. When an inducing agent is prescribed with another medication, the dosage of the other medication may need to be adjusted since the rate of metabolism is increased and the effect of the medication reduced. This can lead to a therapeutic failure of the medication. Conversely, if a medication is taken with an agent that inhibits it metabolism, then the drug level can rise and possibly result in a harmful or adverse effect. Information regarding a drug's CYP450 metabolism and its potential for inhibition or induction can be found on the drug label and accessed through the U.S. Food and Drug Administration (FDA) or manufacturer's websites.
When we assess our patients and provide management modalities, these are implemented within a framework of the patient's heritage, race, and culture. This is also true in pharmacology as well (i.e., "pharmacogenetics"). This concept is important to examine since we know that there exists genetic variability, which may influence a patient's response to commonly prescribed drug classes. This genetic variability can be defined as polymorphism. Seven percent of Caucasians and two to seven percent of African Americans are poor metabolizers of drugs dependent on CYP2D6, which metabolizes many beta blockers, antidepressants, and opioids. This is because the drug's metabolism via CYP450 enzymes exhibits genetic variability.
Recently, researchers have studied the genetic variability in metabolism among women who were prescribed tamoxifen and medications that inhibit the CYP2D6 enzyme. To review, tamoxifen is biotransformed to the potent anti-estrogen, endoxifen, by this enzyme. CYP2D6 genetic variation (individuals considered extensive metabolizers versus poor metabolizers) and inhibitors of the enzyme markedly reduce endoxifen plasma concentrations in tamoxifen-treated patients.
The researchers concluded that CYP2D6 metabolism is an "independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women". Do oncology patients come to us with only their cancer and its treatment? No, they come with multifaceted dimensions and co-morbid conditions such as hypertension, dyslipidemia, depression, seizure disorders, etc. For example, several antidepressants (paroxetine [Paxil] and fluoxetine [Prozac]) are inhibitors of metabolism when given with drugs metabolized through the CYP2D6 enzyme, such as haloperidol (Haldol), metoprolol (Lopressor), and hydrocodone. Thus, the therapeutic response can be accentuated. Medications that inhibit the CYP3A4 enzyme such as amiodarone and antifungals, can affect the therapeutic response of fentanyl, alprazolam (Xanax), and numerous statins; as a result, the effect of these drugs can be enhanced leading to potential toxic levels.
At times, these CYP 450 inducers and inhibitors are commonly ingested items such grapefruit juice and tobacco. In the case of grapefruit juice, there are numerous medications known to interact with grapefruit juice including statins, antiarrhythmic agents, immunosuppressive agents, and calcium channel blockers. Furthermore, the inhibition of the enzyme system seems to be dose dependent; thus, the more a patient drinks, the more the inhibition that occurs. Additionally, the effects can last for several days if grapefruit juice is consumed on a regular basis. Luckily, the effect of this is not seen with other citrus juices.
Hopefully, this brief review has opened the door to your inquisitive nature on how the liver's enzyme system is effected by numerous medications and why some patients experience clinically significant unanticipated adverse reactions or therapeutic failures.
|Alosetron, Amitriptyline, Clozapine, Cyclobenzaprine, Desipramine, Diazepam, Fluvoxamine, Imipramine, Mexiletine, Mirtazapine, Olanzapine, Propranolol, Ropinirole, Theophylline, (R)-Warfarin||Cimetidine, Ciprofloxacin, Fluvoxamine, Ketoconazole, Lidocaine, Mexiletine||Carbamazepine, Cigarette smoke, Phenobarbital, Rifampin|
|Celecoxib, Glimepiride, Glipizide, Losartan, Montelukast, Nateglinide, Phenytoin, Sulfamethoxazole, Voriconazole, (S)-Warfarin||Amiodarone, Delavirdine, Efavirenz, Fluconazole, Fluvastatin, Ketoconazole, Sulfamethoxazole, Zafirlukast||Carbamazepine, Phenobarbital, Phenytoin, Rifampin|
|Citalopram, Diazepam, Escitalopram, Esomeprazole, Imipramine, Lansoprazole, Nelfinavir, Omeprazole, Pantoprazole, Phenytoin, Rabeprazole, Voriconazole||Delavirdine, Efavirenz, Esomeprazole, Fluoxetine, Fluvoxamine, Lansoprazole, Omeprazole, Rabeprazole, Sertraline, Ticlopidine||Carbamazepine, Phenytoin, Rifampin|
|Amitriptyline, Aripiprazole, Atomoxetine, Codeine, Desipramine, Dextromethorphan, Flecainide, Fluoxetine, Haloperidol, Imipramine, Lidocaine, Metoprolol, Mexiletine, Mirtazapine, Nefazodone, Nortriptyline, Oxycodone, Paroxetine, Propafenone, Propranolol, Risperidone, Ritonavir, Tramadol. Venlafaxine||Amiodarone, Cimetidine, Clozapine, Delavirdine, Desipramine, Fluoxetine, Haloperidol, Lidocaine, Methadone, Paroxetine, Pimozide, Quinidine, Ritonavir, Sertraline, Ticlopidine||None|
|Alprazolam, Amiodarone, Aprepitant, Aripiprazole, Atorvastatin, Buspirone, Calcium channel blockers, Carbamazepine, Cilostazol, Citalopram, Clarithromycin, Clonazepam, Cyclosporine, Dapsone, Delavirdine, Diazepam, Disopyramide, Efavirenz, Ergot derivatives, Erlotinib, Erythromycin, Escitalopram, Estrogens, Fentanyl, Geftinib, Glucocorticoids, Imatinib, Indinavir, Irinotecan, Itraconazole, Ketoconazole, Lansoprazole, Lidocaine, Losartan, Lovastatin, Methadone, Midazolam, Mirtazapine, Montelukast, Nateglinide, Nefazodone, Nelfinavir, Nevirapine, Ondansetron, Paclitaxel, Pimozide, Protease inhibitors, Quetiapine, Quinidine, Repaglinide, Rifabutin, Sibutramine, Sildenafil, Simvastatin, Sirolimus, Tacrolimus, Tadalafil, Tamoxifen, Theophylline, Tiagabine, Ticlopidine, Vardenafil, (R)-Warfarin, Zolpidem, Zonisamide||Amiodarone, Aprepitant, Cimetidine, Clarithromycin, Cyclosporine, Delavirdine, Diltiazem, Efavirenz, Erythromycin, Fluconazole, Grapefruit juice, Imatinib, Indinavir, Itraconazole, Ketoconazole, Metronidazole, Nefazodone, Nelfinavir, Quinidine, Ritonavir, Saquinavir, Sertraline, Verapamil, Voriconazole||Carbamazepine, Efavirenz, Nevirapine, Phenobarbital, Phenytoin, Rifabutin, Rifampin, St. John's wort|
Jamison T. (Winter 2008). Oncology Nursing Society, Metro Detroit Chapter Newsletter, Volume XXIII, Issue 1.
Lynch, T. & Price, A (2007). The effect of P450 metabolism on drug response, interactions, and adverse effects. American Family Physician, 76(3), 391397.
Arcangelo, V. P. & Peterson, A. M. (2006). Pharmacotherapeutics for Advanced Practice: A Practical Approach. (2nd ed). Philadelphia: Lippincott Williams and Wilkins.
Goetz, M., Knox, S, Suman, V., & Rae, J. (2007). The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Research and Treatment. 101(1), 113122.
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