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CYTOCHROME P450 2C19

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  • TOP
  • ACRONYMS AND DEFINITIONS
  • CYTOCHROME P450
    • CYP2C19 poor metabolizers
  • IMPORTANT POINTS ABOUT DRUG INTERACTIONS
  • CYP2C19 INDUCERS
  • CYP2C19 INHIBITORS
  • CYP2C19 SUBSTRATES
  • BIBLIOGRAPHY

  • OTHER RELATED PAGES
    • Cytochrome P450 1A2
    • Cytochrome P450 2B6
    • Cytochrome P450 2C8
    • 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 CYP2C19 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.)

  • CYP2C19 POOR METABOLIZERS
    • Different forms of a gene are called alleles. Individuals and populations can vary in the alleles they carry for a gene.
    • Variations in alleles that code for CYP enzymes can affect the performance of these enzymes. Some alleles may decrease the activity of the enzyme (loss-of-function alleles), while other alleles may increase the activity.
    • Studies have shown that the prevalence of CYP2C19 alleles varies by ethnicity, and these variations affect the metabolic activity of the CYP2C19 enzyme
    • One loss-of-function allele leads to a 47% reduction in CYP2C19 activity, and two loss-of-function alleles leads to a 65% reduction
    • People with one loss-of-function allele are considered "intermediate metabolizers," and people with two loss-of-function alleles are considered "poor metabolizers" [12]
    • CYP2C19 metabolizer-status is particularly important because the widely prescribed antiplatelet agent clopidogrel (Plavix®) must be metabolized by CYP2C19 to become active (see clopidogrel and CYP2C19 poor metabolizers)

      • Prevalence of at least one loss-of-function allele by ethnicity (intermediate metabolizers):
        • Asians 51 - 55%
        • African-Americans 33 - 40%
        • Caucasians 24 - 30%
        • Mexican-Americans 18% [12]
      • Prevalence of two loss-of-function alleles by ethnicity (poor metabolizers):
        • Chinese 14%
        • African-Americans 4%
        • Caucasians 2% [13]

  • 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

  • CYP2C19 INDUCERS

  • Interaction
    • If Drug A is metabolized by CYP2C19, and it is taken with Drug B, a CYP2C19 inducer, then blood levels of Drug A may be decreased

    • Example:
      • Drug A is metabolized by CYP2C19. Drug B is a CYP2C19 inducer.
      • Drug A by itself = normal blood levels
      • Drug A + Drug B = decreased levels of Drug A because Drug B has increased CYP2C19 activity

  • CYP2C19 MODERATE INDUCERS

    • Enzalutamide (Xtandi®) [4]
    • Rifampin [1]

  • CYP2C19 INDUCERS (CLASS UNCERTAIN)

    • Tocilizumab (Actemra®) - indirect induction through inflammation suppression [6]
    • Tumor Necrosis Factor inhibitors - indirect induction through inflammation suppression - (adalimumab, Humira®, certolizumab, Cimzia®, etanercept, Enbrel®, golimumab, Simponi®, infliximab, Remicade®) [6]
    • St. John's Wort (Hypericum perforatum) [10,11]

  • CYP2C19 INHIBITORS

  • Interaction
    • If a Drug A is metabolized by CYP2C19, and it is taken with Drug B, a CYP2C19 inhibitor, then blood levels of Drug A may increase

    • Example:
      • Drug A is metabolized by CYP2C19. Drug B is a CYP2C19 inhibitor.
      • Drug A by itself = normal blood levels
      • Drug A + Drug B = increased blood levels of Drug A because Drug B has inhibited CYP2C19

  • CYP2C19 STRONG INHIBITORS

    • Amitriptyline (Elavil®) [9]
    • Clomipramine (Anafranil®) [9]
    • Fluconazole (Diflucan®) [1]
    • Fluvoxamine (Luvox®) [1]
    • Imipramine (Tofranil®) [9]
    • Ticlopidine (Ticlid®) [1]

  • CYP2C19 MODERATE INHIBITORS

    • Esomeprazole (Nexium®) [1]
    • Fluoxetine (Prozac®) [1]
    • Moclobemide [1]
    • Omeprazole (Prilosec®) [1]
    • Voriconazole (Vfend®) [1]

  • CYP2C19 WEAK INHIBITORS

    • Allicin (garlic derivative) [1]
    • Armodafinil (Nuvigil®) [1]
    • Carbamazepine (Tegretol®) [1]
    • Cimetidine (Tagamet®) [1]
    • Desipramine (Norpramin®) [9]
    • Etravirine (Intelence®) [1]
    • Ethinyl estradiol [1]
    • Felbamate [1]
    • Fenofibrate (Tricor®, etc) [4]
    • Fenofibric acid (Trilipix®) [4]
    • Human growth hormone (HGH) [1]
    • Ketoconazole (Nizoral®) [1]
    • Nortriptyline (Pamelor®) [9]
    • Oral contraceptives [1]
    • Topiramate (Topamax®) [4]

  • CYP2C19 INHIBITORS (CLASS UNCERTAIN)

    • Lansoprazole (Prevacid®) [7]
    • Nicardipine (Cardene®) [4]
    • Oxcarbazepine (Trileptal®) [4]
    • Telmisartan (Micardis®) [4]
    • Vilazodone (Viibryd®) - in vitro studies only [4]

  • CYP2C19 SUBSTRATES

  • Interaction
    • CYP2C19 substrates may be affected by CYP2C19 inducers and inhibitors (see above)
    • If two CYP2C19 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 CYP2C19 inhibitors and/or inducers

    • Example:
      • Drug A is metabolized by CYP2C19. Drug B is metabolized by CYP2C19.
      • When Drug A is taken with Drug B they may compete for the CYP2C19 enzyme
      • This competition may affect blood levels of either one or both of the drugs

  • CYP2C19 SENSITIVE SUBSTRATES

    • NOTE: These drugs are known to be significantly affected by CYP2C19 inhibitors/inducers
    • Carisoprodol (Soma®) [4,7]
    • Citalopram (Celexa®) [4]
    • Clobazam (Onfi®) [4]
    • Diazepam (Valium®) [4,7]
    • Flibanserin (Addyi®) - minor substrate [4]
    • Lansoprazole (Prevacid®) [1]
    • Omeprazole (Prilosec®) [1]
    • Phenytoin (Dilantin®) [1]
    • Tofacitinib (Xeljanz®) [4]

  • CYP2C19 SUBSTRATES

    • Amitriptyline (Elavil®) [7]
    • Apixaban (Eliquis®) [4]
    • Arformoterol (Brovana®) [4]
    • Chloramphenicol [2]
    • Clomipramine (Anafranil®) [7]
    • Clopidogrel (Plavix®) [4]
    • Cyclophosphamide [2]
    • Doxazosin (Cardura®, Cardura XL®) [4, Cardura XL® PI]
    • Fluoxetine (Prozac®) [7]
    • Formoterol (Foradil®) [4]
    • Imipramine (Tofranil®) [7]
    • Indomethacin (Indocin®) [2]
    • Methadone [4]
    • Nelfinavir (Viracept®) [7]
    • Nilutamide (Nilandron®) [2]
    • Nortriptyline (Pamelor®) [7]
    • Ospemifene (Osphena®) [4]
    • Pantoprazole (Protonix®) [1]
    • Prasugrel (Effient®) [4]
    • Praziquantel (Biltricide®) [3]
    • Primidone (Mysoline®) [2]
    • Progesterone [2]
    • Proguanil (Malarone®) [7]
    • Propranolol (Inderal®) [4]
    • Rabeprazole (Aciphex®) [7]
    • Sertraline (Zoloft®) [7]
    • Suvorexant (Belsomra®) (minor substrate) [4]
    • Teniposide [2]
    • Terbinafine (Lamisil®) [4]
    • Timolol (Timoptic®, Blocadren®) (minor substrate) [14]
    • Voriconazole (Vfend®) [4]
    • Warfarin (Coumadin®) [2]

  • BIBLIOGRAPHY

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

  • #     PMID
  • 1 - FDA drug development and drug interactions - CLICK HERE
  • 2 - 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].
  • 3 - SuperCYP
  • 4 - Manufacturer's Package Insert
  • 5 - PubMed ID 11956508
  • 6 - PubMed ID 11602509
  • 7 - PubMed ID 12222994
  • 8 - PubMed ID 21060077
  • 9 - PubMed ID 17471183
  • 10 - Carisoprodol PI
  • 11 - PubMed ID 22606944
  • 12 - PubMed ID 21060077
  • 13 - Clopidogrel PI
  • 14 - PMID 17461033 Timolol metabolism