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CYTOCHROME P450 2D6

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  • TOP
  • ACRONYMS AND DEFINITIONS
  • CYTOCHROME P450
    • Rapid metabolizers and codeine / dihydrocodeine
  • IMPORTANT POINTS ABOUT DRUG INTERACTIONS
  • CYP2D6 INDUCERS
  • CYP2D6 INHIBITORS
  • CYP2D6 SUBSTRATES
  • BIBLIOGRAPHY

  • OTHER RELATED PAGES
    • Cytochrome P450 1A2
    • Cytochrome P450 2B6
    • Cytochrome P450 2C19
    • Cytochrome P450 2C8
    • Cytochrome P450 2C9
    • 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 CYP2D6 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."
    • Some people have genes that produce CYP enzymes that are more effective. These people are often referred to as "rapid metabolizers." Rapid metabolizers may experience toxicity with some medications (see rapid metabolizers below)
    • Gene variations in CYP enzymes can affect how an individual metabolizes a drug

  • RAPID METABOLIZERS AND CODEINE/DIHYDROCODEINE
    • Codeine is metabolized by CYP2D6 to morphine. Dihydrocodeine is metabolized by CYP2D6 to dihydromorphine.
    • CYP2D6 rapid metabolizers may experience opiate toxicity (e.g. respiratory depression) when they are given codeine/dihydrocodeine because they achieve rapid and high levels of morphine/dihydromorphine
    • Respiratory depression and death have occurred in children who received codeine after surgery. These children were found to be ultra-rapid CYP2D6 metabolizers.

    • Prevalence of ultra-rapid CYP2D6 metabolizers by ethnicity:
      • North Africans, Ethiopians, and Arabs - 16 - 28%
      • African-Americans - 3%
      • Caucasians - 1 - 10%
      • Chinese and Japanese - 0.5 - 1%
      • Hispanics - 0.5 - 1% [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

  • CYP2D6 INDUCERS

  • INTERACTION
    • If Drug A is metabolized by CYP2D6, and it is taken with Drug B, a CYP2D6 inducer, then blood levels of Drug A may be decreased

    • Example:
      • Drug A is metabolized by CYP2D6. Drug B is a CYP2D6 inducer.
      • Drug A by itself = normal blood levels
      • Drug A + Drug B = decreased levels of Drug A because Drug B has increased CYP2D6 activity

  • CYP2D6 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]

  • CYP2D6 INHIBITORS

  • INTERACTION
    • If a Drug A is metabolized by CYP2D6, and it is taken with Drug B, a CYP2D6 inhibitor, then blood levels of Drug A may increase

    • Example:
      • Drug A is metabolized by CYP2D6. Drug B is a CYP2D6 inhibitor.
      • Drug A by itself = normal blood levels
      • Drug A + Drug B = increased blood levels of Drug A because Drug B has inhibited CYP2D6

  • CYP2D6 strong inhibitors

    • Bupropion (Wellbutrin®) [1]
    • Fluoxetine (Prozac®) [1]
    • Metoclopramide (Reglan®) [8]
    • Paroxetine (Paxil®) [1]
    • Quinidine [1]

  • CYP2D6 moderate inhibitors

    • Cinacalcet (Sensipar®) [1]
    • Dronedarone (Multaq®) [6]
    • Duloxetine (Cymbalta®) [1]
    • Mirabegron (Myrbetriq®) [6]
    • Terbinafine (Lamisil®) [1]

  • CYP2D6 weak inhibitors

    • Amiodarone (Cordarone®) [1]
    • Amphetamines (in vitro evidence) [6]
    • Asenapine (Saphris®) [6]
    • Celecoxib (Celebrex®) [1,6]
    • Cimetidine (Tagamet®) [1]
    • Desipramine (Norpramin®) [11]
    • Desvenlafaxine (Pristiq®) [1]
    • Diltiazem (Cardizem®) [1]
    • Diphenhydramine (Benadryl®) [1]
    • Echinacea [1]
    • Escitalopram (Lexapro®) [1]
    • Febuxostat (Uloric®) [1,6]
    • Gefitinib (Iressa®) [1]
    • Hydralazine (Apresoline®) [1]
    • Hydroxychloroquine (Plaquenil®) [1]
    • Imatinib (Gleevec®) [1]
    • Imipramine (Tofranil®) [11]
    • Methadone [1]
    • Nortriptyline (Pamelor®) [11]
    • Oral contraceptive pills [1]
    • Propafenone (Rythmol®) [1]
    • Ranitidine (Zantac®) [1]
    • Ritonavir (Norvir®) [1]
    • Sertraline (Zoloft®) [1]
    • Telithromycin (Ketek®) [1]
    • Venlafaxine (Effexor®) [6]
    • Verapamil (Calan®, Isoptin®, etc.) [1]

  • CYP2D6 inhibitors (class uncertain)

    • Amitriptyline (Elavil®) [3]
    • Chlorpheniramine (Chlor-Trimeton®) [7]
    • Chlorpromazine (Thorazine®) [8]
    • Citalopram (Celexa®) [8]
    • Clobazam (Onfi®) [6]
    • Clomipramine (Anafranil®) [2]
    • Cobicistat (part of Stribild®) [6]
    • Doxepin [2,9]
    • Fluphenazine [8]
    • Fluvoxamine (Luvox®) [8]
    • Haloperidol (Haldol®) [8]
    • Hydroxychloroquine (Plaquenil®) (possible, not well-defined) [12]
    • Hydroxyzine (Vistaril®) [2,10]
    • Lorcaserin (Belviq®) [6]
    • Niacin (Niaspan®, Slo-Niacin®) [5]
    • Nicardipine (Cardene®) [6]
    • Peginterferon alfa-2b (PegIntron®) [6]
    • Perphenazine [8]
    • Sertraline (Zoloft®) [8]
    • Thioridazine (Mellaril®) [8]
    • Ticlopidine (Ticlid®) [2, 8]
    • Vilazodone (Viibryd®) - in vitro studies only [6]

  • CYP2D6 SUBSTRATES

  • INTERACTION
    • CYP2D6 substrates may be affected by CYP2D6 inducers and inhibitors (see above)
    • If two CYP2D6 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 CYP2D6 inhibitors and/or inducers

    • Example:
      • Drug A is metabolized by CYP2D6. Drug B is metabolized by CYP2D6.
      • When Drug A is taken with Drug B they may compete for the CYP2D6 enzyme
      • This competition may affect blood levels of either one or both of the drugs

  • CYP2D6 sensitive substrates

    • NOTE: These drugs are known to be significantly affected by CYP2D6 inhibitors / inducers
    • Amphetamines (Adderall®, Vyvanse®, etc.) [6]
    • Aripiprazole (Abilify®) [6]
    • Atomoxetine (Strattera®) [1,6]
    • Brexpiprazole (Rexulti®) [6]
    • Codeine (see CYP2D6 rapid metabolizers and codeine above) [8]
    • Desipramine (Norpramin®) [1]
    • Dextromethorphan (Robitussin DM®, etc.) [1]
    • Dihydrocodeine (see CYP2D6 rapid metabolizers and dihydrocodeine above) [6]
    • Iloperidone (Fanapt®) [6]
    • Metoprolol (Toprol®) [1]
    • Nebivolol (Bystolic®) [1]
    • Perphenazine [1]
    • Propafenone (Rythmol®) [6, 8]
    • Risperidone (Risperdal®) [6, 8]
    • Timolol (Timoptic®, Blocadren®) [6]
    • Tolterodine (Detrol®) [1]
    • Venlafaxine (Effexor®) [1]
    • Vortioxetine (Brintellix®) [6]
    • Thioridazine (Mellaril®) - has a narrow therapeutic window [8]

  • CYP2D6 substrates

    • Amitriptyline (Elavil®) [8]
    • Arformoterol (Brovana®) [6]
    • Cariprazine (Vraylar®) (minor substrate) [6]
    • Carvedilol (Coreg®) [6]
    • Chlorpheniramine (Chlor-Trimeton®) [8]
    • Chlorpromazine (Thorazine®) [8]
    • Ciclesonide (Alvesco®, Omnaris®) [6]
    • Clomipramine (Anafranil®) [8]
    • Clonidine (Catapres®) [4]
    • Clozapine (Clozaril®) [8]
    • Donepezil (Aricept®) [8]
    • Doxazosin (Cardura®, Cardura XL®) [6, Cardura XL® PI]
    • Doxepin [8]
    • Duloxetine (Cymbalta®) [8]
    • Flecainide (Tambocor®) [6]
    • Fluoxetine (Prozac®) [8]
    • Fluphenazine [8]
    • Fluvoxamine (Luvox®) [8]
    • Formoterol (Foradil®) [6]
    • Haloperidol (Haldol®) [8]
    • Imipramine (Tofranil®) [8]
    • Ivermectin (Stromectol®) - in vitro only - minor substrate [6]
    • Metaxalone (Skelaxin®) [6]
    • Methadone (minor substrate) [6]
    • Metoclopramide (Reglan®) [8]
    • Mirtazapine (Remeron®) [6]
    • Mexiletine [6]
    • Nicardipine (Cardene®) [6]
    • Nortriptyline (Pamelor®) [8]
    • Olanzapine (Zyprexa®) (minor substrate) [6]
    • Ondansetron (Zofran®) [8]
    • Oxycodone (Oxycontin®, Percocet®) (minor substrate) [2,6]
    • Paliperidone (Invega®) (minor substrate)[6]
    • Paroxetine (Paxil®) [8]
    • Promethazine (Phenergan®) [8]
    • Propranolol (Inderal®) [6]
    • Tamoxifen [2,8]
    • Tamsulosin (Flomax®) [6]
    • Tiotropium (Spiriva®) (minor substrate) [6]
    • Tramadol (Ultram®) [6,8]
    • Trimipramine (Surmontil®) [8]
    • Umeclidinium (Anoro Ellipta®) [6]

  • 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  -  PMID 20570945
  • 5 -   PMID 15081432
  • 6 -   Manufacturer's package insert (for drug listed)
  • 7 -   PMID 11936702
  • 8 -   PMID 19601803
  • 9 -   PMID 15520506
  • 10 - PMID 9616188
  • 11 - PMID 17471183
  • 12 - PMID 10848718
  • 13 - Codeine sulfate PI