Cytochrome enzymes and drug interactions

As nurses, we’re used to administering lots of of several types of medications. We may even give patients 5 or 6 drugs at a time, or much more throughout the day, with the expectation that we all know the dosage, mechanism, negative effects, and drug interactions. All nurses, especially those with advanced practice and prescribing credentials, have the extra responsibility of understanding that every patient may respond otherwise to medications resulting from inherited cytochrome P450 enzymes.

Cytochrome P450 (CYP450) are oxidative enzymes and the primary system of drug metabolism. These enzymes, produced within the liver, small intestine, lungs and placenta, also play a job within the production of cholesterol, steroids, prostacyclin and thromboxane A2. There are 58 identified CYP genes, but roughly eight (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) are accountable for the metabolism of most drugs. A drug metabolized by the CYP450 enzyme is a, and the speed of metabolism is influenced by CYP450 (Crawford, 2017).

Inducers are drugs that act on the liver to extend the speed of drug metabolism, thereby reducing plasma drug concentrations and potentially causing subtherapeutic effects. Inducers increase CYP450 enzyme activity by increasing enzyme synthesis (Lynch and Price, 2007). This effect is normally delayed resulting from the half-life of the drug. A drug reminiscent of rifampicin (Rifadin) has a brief half-life and should reduce the concentration of one other drug metabolized by CYP2C9 inside 24 hours. Phenobarbital, an inducer with a protracted half-life, may reduce drug concentrations per week later. The drug might also be metabolized by the identical CYP450 enzyme that it induces.

Inhibitors are drugs that act on the liver to scale back or block the metabolic activity of a number of CYP450 enzymes. Slowed metabolism may increase drug plasma concentrations and potentially cause negative effects and toxicity. The dose of the drug and its ability to bind to the enzyme will influence the degree of inhibition. For example, 50 mg of sertraline (Zoloft) is a gentle CYP2D6 inhibitor, while a 200 mg dose is a powerful inhibitor. A drug might also be metabolized by the identical enzyme and inhibited, or it could be metabolized by one enzyme and inhibit one other enzyme (Lynch and Price, 2007). The inhibitory response is normally immediate and is essentially the most common mechanism resulting in drug-drug interactions because multiple drugs may compete for a similar CYP450 energetic site (Deodhar et al., 2020). Information regarding drug metabolism by the CYP450 isoenzyme and its potential for inhibition or induction will be found on the drug label.

Genetic variation, or polymorphism, in these enzymes in a person affects an individual’s response to many common medications, including beta-blockers and antidepressants. Polymorphisms in CYP genes may lead to reduced/absent or increased/excessive metabolism of the compound (Tantisira and Weiss, 2021). People with intermediate and poor metabolism are at increased risk of toxicity and negative effects resulting from drug accumulation. These patients have hypersensitivity or low tolerance to certain medications and should due to this fact require reduced doses or complete avoidance of the drug (McDonnell and Dang, 2013). This might also occur if a CYP450 enzyme inhibitor is added to therapy, if the drug has a narrow safety range, or if its metabolism relies on just one enzyme. To avoid drug interactions, it could be obligatory to fastidiously adjust the dose, monitor clinical effects, or switch to an alternate drug with a distinct metabolic pathway (Deodhar et al., 2020).

Drugs absorbed from the small intestine are sometimes first metabolized by CYP3A4. Grapefruit juice is a CYP3A4 inhibitor and should reduce the metabolism of many drugs, increasing the quantity of drug available for absorption and enhancing its effects (McDonnel and Dang, 2013). Grapefruit can affect the consequences of 85 medications, and only affects medications which might be taken by mouth and absorbed within the stomach or intestines. After exposure to grapefruits, half of the enzyme activity returns to normal inside 24 hours, but full recovery of activity may take up to a few days if grapefruits are consumed usually. In individuals who naturally have low levels of CYP3A4, grapefruit can completely stop the metabolism of the drug and cause drug toxicity. People with naturally higher levels of CYP3A4 can eat grapefruit with minimal effect on drug levels or antagonistic reactions.

Grapefruit may reduce the effect of clopidogrel on platelets or limit the effectiveness of the allergy medicine fexofenadine. However, grapefruit may increase the consequences of lovastatin, simvastatin and atorvastatin to toxic levels. Patients taking statins which might be metabolized by CYP3A4 should avoid consuming grapefruit or take statins that are usually not metabolized by this enzyme.

Lynch and Price (2007) recommend the next key strategies for clinical practice:

• If patients show unusual sensitivity or resistance to drugs at normal doses, genetic differences in CYP450 metabolism ought to be taken into consideration.
• Patients ought to be monitored closely for antagonistic effects or therapeutic failure when a powerful CYP450 enzyme inhibitor or inducer is added to drugs metabolized by a number of CYP450 enzymes.
• Assess for severe toxicity if drugs that inhibit CYP450 enzymes are added to the next drugs:
  • Atypical antipsychotics
  • Benzodiazepines
  • Cyclosporine (sand resistant)
  • Statins
  • Warfarin (Coumadin)
• Caution ought to be exercised when adding the next substances to patients’ medications as they’re known to cause significant drug interactions involving the CYP450 enzyme:
  • Amiodarone (cordaron)
  • Antiepileptic drugs
  • Antidepressants
  • Antituberculosis drugs
  • Grapefruit juice
  • Macrolide and ketolide antibiotics
  • Non-dihydropine calcium channel blockers
  • Protease inhibitors

CYP450 is a posh and significant component of drug metabolism and is the source of many drug interactions through inhibition, induction, and competition for common enzymatic pathways by different drugs (McDonnell and Dang, 2013). Genetic variability of CYPs can also be a major reason behind unpredictable drug effects. Awareness and understanding of medication involved in common CYP pathways will help nurses and providers predict and forestall potential drug interactions.

Listing all medications and their interactions with CYP450 is beyond the scope of this blog. However, the Flockhart Table™ drug interaction table provides a comprehensive overview of medication with CYP450 pharmacogenetics organized by substrate, inhibitor, or inducer. The board will be found online at: https://drug-interactions.medicine.iu.edu/MainTable.aspx.

Crawford, D. (2017). Food and drug interactions. , (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., and Michaud, V. (2020). Mechanisms of CYP450 inhibition: understanding drug-drug interactions following mechanism-based inhibition in clinical practice. , (9), 846. https://doi.org/10.3390/pharmaceutics12090846

Lynch, T., & Price, A. (2007). Influence of cytochrome P450 metabolism on drug response interactions and negative effects. . (3), 391-396. https://www.aafp.org/afp/2007/0801/p391.html

McDonnell, A. M., and Dang, C. H. (2013). Basic overview of the cytochrome p450 system. , (4), 263–268. https://doi.org/10.6004/jadpro.2013.4.4.7

Tantisira, K., & Weiss, S. T. (2021, April 22). Pharmacogenomics review. . https://www.uptodate.com/contents/overview-of-pharmacogenomics