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CYTOCHROME P450 2C8

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  • TOP
  • ACRONYMS AND DEFINITIONS
  • CYTOCHROME P450
  • IMPORTANT POINTS ABOUT DRUG INTERACTIONS
  • CYP2C8 INDUCERS
  • CYP2C8 INHIBITORS
  • CYP2C8 SUBSTRATES
  • BIBLIOGRAPHY

  • OTHER RELATED PAGES
    • Cytochrome P450 1A2
    • Cytochrome P450 2B6
    • Cytochrome P450 2C19
    • Cytochrome P450 2C9
    • Cytochrome P450 2D6
    • Cytochrome P450 3A4/5
    • P-glycoprotein
    • Organic Anion Transporting Polypeptide (OATP)
    • Organic Cation Transporter (OCT2)
    • Transport protein illustration



  • PLEASE NOTE

    • The information presented here is NOT A COMPLETE LIST of CYP2C8 inducers, inhibitors, and substrates
    • An easy way to quickly search the drug lists is with your browser's Search/Find (Ctrl+F) tool
    • 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
    • FDA - U.S. Food and Drug Administration
    • Substrate - a drug that is metabolized by a certain enzyme is a substrate of that enzyme
      •

  • CYTOCHROME P450

  • CYTOCHROME P450
    • 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 (ex. 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
      • Some drugs affect the action of CYP enzymes:
        • Inducers - increase the activity of CYP enzymes
        • Inhibitors - block the action of CYP enzymes
        • When CYP inducers or inhibitors are taken with other medications that are metabolized by the same enzyme, they can alter the metabolism of that medication
        • 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 and also inhibit or induce 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
        • 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
      • Compounding can also occur between CYP enzymes and cell transport systems (ex. p-glycoprotein, OAT, etc.)

  • 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 include the following:
      • 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, or 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

  • Interaction
    • If Drug A is metabolized by CYP2C8, and it is taken with Drug B, a CYP2C8 inducer, then blood levels of Drug A may be decreased

    • Example:
      • Drug A is metabolized by CYP2C8. Drug B is a CYP2C8 inducer.
      • Drug A by itself = normal blood levels
      • Drug A + Drug B = decreased levels of Drug A because Drug B has increased CYP2C8 activity

  • CYP2C8 MODERATE INDUCERS

    • Rifampin [6]

  • CYP2C8 INDUCERS (CLASS UNCERTAIN)

    • 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

  • Interaction
    • If a Drug A is metabolized by CYP2C8, and it is taken with Drug B, a CYP2C8 inhibitor, then blood levels of Drug A may increase

    • Example:
      • Drug A is metabolized by CYP2C8. Drug B is a CYP2C8 inhibitor.
      • Drug A by itself = normal blood levels
      • Drug A + Drug B = increased blood levels of Drug A because Drug B has inhibited CYP2C8

  • 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 UNCERTAIN)

    • 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]
    • Trimethoprim (found in Bactrim®, Septra®, etc) [6,7]
    • Vilazodone (Viibryd®) - in vitro studies only [3]

  • CYP2C8 SUBSTRATES

  • Interaction
    • CYP2C8 substrates may be affected by CYP2C8 inducers and inhibitors (see above)
    • If two CYP2C8 substrates are taken together, they may compete for the enzyme and the metabolism of one or both of the drugs may be affected
    • Sensitive substrates are drugs that are known to be significantly affected by CYP2C8 inhibitors and/or inducers

    • Example:
      • Drug A is metabolized by CYP2C8. Drug B is metabolized by CYP2C8.
      • When Drug A is taken with Drug B they may compete for the CYP2C8 enzyme
      • This competition may affect blood levels of either one or both of the drugs

  • 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

  • What is PMID?
  • PI = Manufacturer's Package Insert

  • #     PMID
  • 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