As nurses, we are accustomed to administering hundreds of different types of medications. We might even give patients five or six medications at a time and even more throughout the day, with the expectation that we know the dosage, mechanism, side effects and drug-drug interactions. All nurses, particularly those in advanced practice with prescribing privileges, have an added responsibility of understanding that each patient may react to drugs differently based on their inherited cytochrome P450 enzymes.
What are cytochrome enzymes?
Cytochrome P450 (CYP450) are oxidative enzymes and the primary system for drug metabolism. Produced in the liver, small intestine, lungs, and placenta, these enzymes also play a role in the production of cholesterol, steroids, prostacyclin, and thromboxane A2. There are 58 identified CYP genes, however about eight (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) are responsible for metabolizing most medications. A drug that is metabolized by a CYP450 enzyme is a substrate
and the rate of metabolization is affected by inducers
of CYP450 (Crawford, 2017).
Inducers are drugs that act on the liver to increase rates of drug metabolism, thereby decreasing plasma drug levels and potentially causing subtherapeutic effects. Inducers increase CYP450 enzyme activity by increasing enzyme synthesis (Lynch & Price, 2007). This effect is usually delayed based on the drug’s half-life. A drug such as rifampin (Rifadin) has a short half-life and can decrease the concentration of another drug metabolized by CYP2C9 within 24 hours. Phenobarbital, an inducer with a long half-life, might decrease the concentration of a drug one week later. A drug can also be metabolized by the same CYP450 enzyme that it induces.
Inhibitors are drugs that act on the liver to decrease or block the metabolic activity of one or more CYP450 enzymes. The reduced metabolism may increase plasma levels of a drug and potentially cause adverse reactions and toxicity. The drug dose and its ability to bind to the enzyme will impact the degree of inhibition. For example, 50 mg of sertraline (Zoloft) is a mild inhibitor of CYP2D6 while a 200 mg dose is a strong inhibitor. A drug can also be metabolized by and inhibit the same enzyme, or it can be metabolized by one enzyme and inhibit another enzyme (Lynch & Price, 2007). The inhibitory reaction is typically immediate and the most common mechanism leading to drug-drug interactions since multiple drugs can compete for the same CYP450 active site (Deodhar et al., 2020). Information regarding a drug’s CYP450 metabolism and its potential for inhibition or induction can be found on the drug label.
An individual’s genetic variability, or polymorphism, of these enzymes affects a person’s response to many common drugs including beta blockers and antidepressants. Polymorphism in CYP genes may cause either a decreased/absent or an increased/excessive metabolism of a compound (Tantisira & Weiss, 2021). Intermediate and poor metabolizers are at increased risk for toxicity and adverse effects due to drug accumulation. These patients demonstrate hypersensitivity or low tolerance to specific drugs and subsequently may require reduced doses or must avoid the drug completely (McDonnell & Dang, 2013). This can also occur if a CYP450 enzyme inhibitor is added to the therapy, if a drug has a narrow safety range or is dependent on only one enzyme for metabolism. Titrating the dose carefully, monitoring for clinical effects, or switching to an alternate drug with a different metabolic pathway may be needed to avoid drug interactions (Deodhar et al., 2020).
What’s Up with Grapefruit? (Crawford, 2017)
Drugs absorbed from the small intestine are often first metabolized by CYP3A4. Grapefruit juice is an inhibitor of CYP3A4 and may decrease the metabolism of many medications, increasing the amount of drug available for absorption and potentiating the drug effect (McDonnel & Dang, 2013). Grapefruit can impact the action of 85 medications, and only affects medications taken orally and absorbed in the stomach or intestines. After exposure to grapefruit, half of the enzyme activity recovers within 24 hours, however it may take up to three days for a full recovery if grapefruit is regularly consumed. For individuals who naturally have low levels of CYP3A4, grapefruit may stop drug metabolism completely and could cause drug toxicity. Individuals with naturally higher levels of CYP3A4 may be able to eat grapefruit with minimal effect on drug levels or adverse reactions.
Grapefruit may decrease the platelet effects of clopidogrel or limit the effectiveness of the allergic medication fexofenadine. In contrast, grapefruit may increase the effects of lovastatin, simvastatin, and atorvastatin to toxic levels. Patients taking a statin medication metabolized by CYP3A4 should avoid grapefruit consumption or take a statin medication that isn’t metabolized by this enzyme.
Lynch and Price (2007) recommend the following key strategies for clinical practice:
- Genetic variations in CYP450 metabolism should be considered when patients exhibit unusual sensitivity or resistance to drug effects at normal doses.
- Monitor patients closely for adverse effects or therapeutic failures when a potent CYP450 enzyme inhibitor or inducer is added to drugs metabolized by one or more CYP450 enzyme.
- Assess for severe toxicity if CYP450 enzyme-inhibiting drugs are added to the following medications:
- Atypical antipsychotics
- Cyclosporine (Sandimmune)
- Warfarin (Coumadin)
- Use caution when adding the following substances to medications that patients are taking as they are known to cause significant CYP450 drug interactions:
- Amiodarone (Cordarone)
- Antiepileptic drugs
- Antitubercular drugs
- Grapefruit juice
- Macrolide and ketolide antibiotics
- Nondihydropine calcium channel blockers
- Protease inhibitors
CYP450 is a complex and critical component of drug metabolism and is the source of many drug interactions due to inhibition, induction, and competition for common enzymatic pathways by different drugs (McDonnell & Dang, 2013). Genetic variability of CYP is also a significant cause of unpredictable drug effects. Awareness and understanding of drugs involved in common CYP pathways will help nurses and providers predict and prevent potential drug interactions.
Listing every drug and their respective CYP450 interaction is beyond the scope of this blog. However, the Drug Interactions Flockhart Table™ is an extensive review of the drugs with CYP450 pharmacogenetics organized by substrate, inhibitor or inducer. The table can be found online at https://drug-interactions.medicine.iu.edu/MainTable.aspx.
Crawford, D. (2017). Food-drug interactions. Nursing Made Incredibly Easy!, 15(2), 49-54. https://doi.org/10.1097/01.NME.0000511844.70516.3a
Deodhar, M., Al Rihani, S. B., Arwood, M. J., Darakjian, L., Dow, P., Turgeon, J., & Michaud, V. (2020). Mechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice. Pharmaceutics, 12(9), 846. https://doi.org/10.3390/pharmaceutics12090846
Lynch , T. & Price, A. (2007). The Effect of Cytochrome P450 Metabolism on Drug Response Interactions, and Adverse Effects. American Family Physician. 76(3), 391-396. https://www.aafp.org/afp/2007/0801/p391.html
McDonnell, A. M., & Dang, C. H. (2013). Basic review of the cytochrome p450 system. Journal of the advanced practitioner in oncology, 4(4), 263–268. https://doi.org/10.6004/jadpro.2013.4.4.7
Tantisira, K. & Weiss, S.T. (2021, April 22). Overview of pharmacogenomics. UpToDate. https://www.uptodate.com/contents/overview-of-pharmacogenomics
Additional Reading and Resources