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- Please note
- The information presented here is NOT A COMPLETE LIST of CYP2C8 inducers, inhibitors, and substrates
- Not all drug interactions are clinically significant. Potential drug interactions should be researched, and medication changes should only be made after consulting a health professional.
- ACRONYMS AND DEFINITIONS
- CYP - Cytochrome P450
- Substrate - a drug that is metabolized by a certain enzyme is a substrate of that enzyme
- CYTOCHROME P450
- Overview
- Cytochrome P450 (often abbreviated "CYP") is a class of enzymes that is involved in the metabolism of many medications
- Cytochrome P450 enzymes are located primarily in the liver
- Cytochrome P450 enzymes are subdivided into classes (e.g. 2D6, 3A4, 2C8, etc.) based on their structure
- Drug metabolism
- Drugs may be metabolized by one subclass of CYP enzyme (ex. 3A only), or they may be metabolized by a number of CYP enzymes (ex. 2C8, 3A4, and 2C19)
- In some cases, one CYP enzyme may be responsible for the majority of the drug's metabolism while other CYP enzymes contribute a nonsignificant amount of metabolism
- Some drugs undergo no CYP metabolism
- CYP drug interactions
- Inducers and Inhibitors
- Inducers - CYP inducers increase the activity of CYP enzymes. This may increase the metabolism of other drugs that are substrates of the enzyme reducing their exposure.
- Inhibitors - CYP inhibitors reduce the activity of CYP enzymes. This may decrease the metabolism of other drugs that are substrates of the enzyme increasing their exposure.
- Certain chemicals and foods (ex. tobacco smoke and grapefruit juice) may also act as CYP inducers and inhibitors
- Drugs may be metabolized by a CYP enzyme while also inhibiting or inducing the enzyme at the same time
- Inducers and inhibitors can be subdivided into strong, moderate, or weak based on how much of an effect they have on the enzyme
- Competitive inhibition
- If two drugs are metabolized by the same CYP enzyme, they may "compete" for the enzyme and this can alter the metabolism of one or both of the drugs
- Compounded interactions
- When a person is taking three or more drugs, the potential for compounded interactions exists
- Compounding can also occur between CYP enzymes and cell transport systems (ex. p-glycoprotein, OAT, etc.)
- Example:
- Drug A is metabolized by CYP2D6 and CYP2C9
- Drug B inhibits CYP2D6. Drug C inhibits CYP2C9
- When Drug A is taken with Drug B, its elimination is partially decreased, but it is not significant
- When Drug A is taken with Drug B and Drug C, its elimination is decreased substantially and the interaction becomes significant
- Genetic factors
- Different genes code for each CYP enzyme
- Since individuals vary in their genetic makeup, their CYP genes may also vary
- Some people have genes that produce CYP enzymes that are less effective
- These people are often referred to as "poor metabolizers"
- Gene variations in CYP enzymes can affect how an individual metabolizes a drug
- IMPORTANT POINTS ABOUT DRUG INTERACTIONS
- Drug interactions are challenging
- Information on drug interactions can be difficult to assimilate
- Certain drug interactions and metabolic pathways are well-documented while many are not
- Factors that can make drug interactions challenging
- New drugs
- When a new drug is being developed, the FDA requires that it be tested for drug interactions with a small number of medications that are known to have significant interactions
- Obviously, there is no way to test a medication in every possible drug combination that may occur. This means most drugs come to market with incomplete drug interaction profiles.
- After a medication is prescribed to a large number of people, other drug interactions are inevitably discovered
- Research
- Much of the research involving drug metabolism and drug interactions occurs in vitro meaning in a lab, or outside of the human body
- Animal models and cell cultures are often used to test drugs for metabolic pathways and interactions
- Findings from in vitro experiments do not always translate into what actually happens in the human body (in vivo)
- Evolving information
- Drug metabolism is an evolving field of medicine and pharmacology
- Researchers are just beginning to understand all the different systems that are involved in how the body metabolizes and eliminates drugs
- Cell transport systems (ex. p-glycoprotein, OAT, etc.) are a relatively new area of pharmacology and information about how these systems affect drug elimination is evolving
- Important points
- Not all drug interactions are known or can be predicted
- Good information on possible drug interactions may not be available
- Not all drug interactions are significant
- Always consult your physician or pharmacist before changing your medication if you are concerned about a possible drug interaction
- CYP2C8 INDUCERS
- CYP2C8 moderate inducers
- Rifampin [6]
- CYP2C8 inducers (class not well-defined)
- Peginterferon alfa-2b (PegIntron®) [3]
- Rifapentine (Priftin®) [3]
- Tocilizumab (Actemra®) - indirect induction through inflammation suppression [3]
- Tumor Necrosis Factor inhibitors - indirect induction through inflammation suppression - (adalimumab, Humira®, certolizumab, Cimzia®, etanercept, Enbrel®, golimumab, Simponi®, infliximab, Remicade®) [3]
- CYP2C8 INHIBITORS
- CYP2C8 strong inhibitors
- Gemfibrozil (Lopid®) [6]
- Clopidogrel (Plavix®) - the acyl-β-glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8 [3]
- CYP2C8 weak inhibitors
- Fluvoxamine (Luvox®) [6]
- Ketoconazole [6]
- CYP2C8 inhibitors (class not well-defined)
- Fenofibrate (Tricor®, Antara®, etc) [2]
- Fenofibric acid (Trilipix®) [3]
- Montelukast (Singulair®) [6]
- Nicardipine (Cardene®) [3]
- Quercetin (a bioflavonoid found in supplements) [6]
- Simvastatin (Zocor®) [7]
- Spironolactone (Aldactone®) [2]
- Teriflunomide (Aubagio®) [3]
- Trimethoprim (found in Bactrim®, Septra®, etc) [6,7]
- Vilazodone (Viibryd®) - in vitro studies only [3]
- CYP2C8 SUBSTRATES
- CYP2C8 sensitive substrates
- NOTE: These drugs are known to be significantly affected by CYP2C8 inhibitors/inducers
- Enzalutamide (Xtandi®) [3]
- Dabrafenib (Tafinlar®) [3]
- Dasabuvir (Viekira Pak™) - major substrate [3]
- Paclitaxel - has a narrow therapeutic window [6]
- Pioglitazone (Actos®) [3]
- Repaglinide (Prandin®) [3,6]
- Rosiglitazone (Avandia®) [3,6]
- Velpatasvir (Epclusa®) [3]
- CYP2C8 substrates
- Amiodarone (Cordarone®) [3,7]
- Apixaban (Eliquis®) [3]
- Chloroquine (Aralen®) [7]
- Febuxostat (Uloric®) [3]
- Fluvastatin (Lescol®) - minor substrate [3,7]
- Ibuprofen (Motrin®, Advil®) [7]
- Loperamide (Imodium®) [7]
- Isotretinoin (Accutane®, Claravis®) (in vitro data only) [3,7]
- Montelukast (Singulair®) in vitro data [3]
- Nicardipine (Cardene®) [3]
- Olodaterol (Striverdi Respimat®) [3]
- Pitavastatin (Livalo®) - minor substrate [3]
- Simvastatin (Zocor®) [7]
- Sitagliptin (Januvia®) [3]
- Terbinafine (Lamisil®) [3]
- Torsemide (Demadex®) [1]
- Verapamil (Calan®, Covera-HS®, Isoptin SR®, Verelan PM®) [7]
- Voxilaprevir (Vosevi™) [3]
- BIBLIOGRAPHY
- 1 - Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed [2011].
- 2 - PubMed ID - 15601807
- 3 - Manufacturer's Package Insert (for drug labeled)
- 4 - PubMed ID - 12642470
- 5 - PubMed ID -11602509
- 6 - FDA drug development and drug interactions - CLICK HERE
- 7 - PubMed ID - 20214592