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CYTOCHROME P450 3A4/5

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  • TOP
  • ACRONYMS AND DEFINITIONS
  • CYTOCHROME P450
  • IMPORTANT POINTS ABOUT DRUG INTERACTIONS
  • CYP3A INDUCERS
  • CYP3A INHIBITORS
  • CYP3A SUBSTRATES
  • BIBLIOGRAPHY

  • OTHER RELATED PAGES
    • Cytochrome P450 1A2
    • Cytochrome P450 2B6
    • Cytochrome P450 2C19
    • Cytochrome P450 2C8
    • Cytochrome P450 2C9
    • Cytochrome P450 2D6
    • 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 CYP3A4/5 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
    • CYP3A - includes both CYP3A4 and CYP3A5
    • 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

  • CYP3A INDUCERS

  • Interaction
    • If Drug A is metabolized by CYP3A, and it is taken with Drug B, a CYP3A inducer, then blood levels of Drug A may be decreased

    • Example:
      • Drug A is metabolized by CYP3A. Drug B is a CYP3A inducer.
      • Drug A by itself = normal blood levels
      • Drug A + Drug B = decreased levels of Drug A because Drug B has increased CYP3A activity

  • CYP3A strong inducers

    • Carbamazepine (Tegretol®) [9]
    • Enzalutamide (Xtandi®) [7]
    • Phenobarbital [5]
    • Phenytoin (Dilantin®) [9]
    • Rifampin [9]
    • St. John's Wort [9]

  • CYP3A moderate inducers

    • Bosentan (Tracleer®) [9]
    • Efavirenz (Sustiva®) [9]
    • Etravirine (Intelence®) [9]
    • Modafinil (Provigil®) [9]
    • Nafcillin [9]

  • CYP3A weak inducers

    • Aprepitant (Emend®) [9]
    • Armodafinil (Nuvigil®) [9]
    • Clobazam (Onfi®) [7]
    • Delafloxacin (Baxdela®) [7]
    • Echinacea [9]
    • Lesinurad (Zurampic®) [7]
    • Pioglitazone (Actos®) [9]
    • Prednisone [9]
    • Rufinamide (Banzel®) [9]
    • Topiramate (Topamax®) [7]

  • CYP3A inducers (class uncertain)

    • Dabrafenib (Tafinlar®) [7]
    • Dexamethasone (Decadron®) [7]
    • Felbamate (Felbatol®) [10]
    • Fosamprenavir (Lexiva®) [7]
    • Griseofulvin (Gris-Peg®) (in vitro evidence) [12]
    • Nevirapine (Viramune®) [7]
    • Oxcarbazepine (Trileptal®) [7]
    • Primidone (Mysoline®) [2]
    • Rifabutin (Mycobutin®) [7]
    • Rifapentine (Priftin®) [7]
    • Tocilizumab (Actemra®) - indirect induction through inflammation suppression [7]
    • Tumor Necrosis Factor inhibitors - indirect induction through inflammation suppression - (adalimumab, Humira®, certolizumab, Cimzia®, etanercept, Enbrel®, golimumab, Simponi®, infliximab, Remicade®) [7]

  • CYP3A INHIBITORS

  • Interaction
    • If a Drug A is metabolized by CYP3A, and it is taken with Drug B, a CYP3A inhibitor, then blood levels of Drug A may increase

    • Example:
      • Drug A is metabolized by CYP3A. Drug B is a CYP3A inhibitor.
      • Drug A by itself = normal blood levels
      • Drug A + Drug B = increased blood levels of Drug A because Drug B has inhibited CYP3A

  • CYP3A strong inhibitors

    • Boceprevir (Victrelis®) [7,9]
    • Clarithromycin (Biaxin®) [1,9]
    • Cobicistat (part of Stribild®) [7]
    • Conivaptan (Vaprisol®)  [9]
    • Fluvoxamine (Luvox®) - likely a strong inhibitor [7]
    • Grapefruit Juice (in large amounts, > 1 liter a day, and in high concentrations) [9]
    • Indinavir (Crixivan®) [1,9]
    • Itraconazole (Sporanox®) [1,9]
    • Ketoconazole (Nizoral®) [1,9]
    • Lopinavir and Ritonavir (Kaletra®) [9]
    • Nefazodone (Serzone®) [1,9]
    • Nelfinavir (Viracept®) [1,9]
    • Posaconazole (Noxafil®) [9]
    • Quinupristin (Synercid®) [7]
    • Ritonavir (Norvir®, Viekira Pak™) [7, 9]
    • Saquinavir (Invirase®) [9] 
    • Telaprevir (Incivek®) [7,9]  
    • Telithromycin (Ketek®) [1,9]
    • Voriconazole (Vfend®) [7,9]

  • CYP3A moderate inhibitors

    • Aprepitant (Emend®) [9]
    • Atazanavir (Reyataz®) [7,9]
    • Ciprofloxacin (Cipro®) [9]
    • Clindamycin (Cleocin®) [7]
    • Darunavir (Prezista®) [9]
    • Diltiazem (Cardizem®, Cartia®, etc) [5,9]
    • Dronedarone (Multaq®) [7]
    • Erythromycin (E.E.S.®, Ery-Tab®, etc) [9]
    • Fluconazole (Diflucan®) [9]
    • Fosamprenavir (Lexiva®)
    • Grapefruit Juice (in lower concentrations and smaller amounts) [9]
    • Imatinib (Gleevec®) [9]
    • Verapamil (Calan®, Covera-HS®, Verelan®, etc) [9]

  • CYP3A weak inhibitors

    • Alprazolam (Xanax®) [9]
    • Amiodarone (Cordarone®) [9]
    • Amlodipine (Norvasc®) [9]
    • Atorvastatin (Lipitor®) [6,9]
    • Bicalutamide (Casodex®) [9]
    • Cilostazol (Pletal®) [9]
    • Cimetidine (Tagamet®) [9]
    • Cyclosporine (Neoral®, Gengraf®, Sandimmune®) [9]
    • Dihydroergotamine (DHE-45®, Migranal®) [5,7]
    • Ergotamine (Cafergot®) [5,7]
    • Fluoxetine (Prozac®) [9]
    • Ginkgo (supplement) [9]
    • Glecaprevir (Mavyret™) [7]
    • Goldenseal (Hydrastis canadensis, root) [9]
    • Grazoprevir (Zepatier®) [7]
    • Imipramine (Tofranil®) [11]
    • Isoniazid [9]
    • Nilotinib (Tasigna®) [9]
    • Oral contraceptives [9]
    • Pibrentasvir (Mavyret™) [7]
    • Ranitidine (Zantac®) [9]
    • Ranolazine (Ranexa®) [9]
    • Tipranavir (Aptivus®) [9]
    • Zileuton (Zyflo®) [9]

  • CYP3A inhibitors (class uncertain)

    • Azithromycin (Zithromax®) [5]
    • Bromocriptine (Cycloset®, Parlodel®) [7]
    • Chloramphenicol [2]
    • Delavirdine (Rescriptor®) [7]
    • Desipramine (Norpramin ®) [5]
    • Danazol [5]
    • Felodipine (Plendil®) [5]
    • Iloperidone (Fanapt®) - in vitro studies only [7]
    • Linagliptin (Tradjenta®) [7]
    • Nicardipine (Cardene®) [5]
    • Nifedipine (Adalat®, Procardia®, etc) [7]
    • Quinidine [5]
    • Simeprevir (Olysio®) - intestinal CYP3A4 inhibitor [7]
    • Zafirlukast (Accolate®) (in vitro data only) [7]

  • CYP3A SUBSTRATES

  • Interaction
    • CYP3A substrates may be affected by CYP3A inducers and inhibitors (see above)
    • If two CYP3A 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 CYP3A inhibitors and/or inducers

    • Example:
      • Drug A is metabolized by CYP3A. Drug B is metabolized by CYP3A.
      • When Drug A is taken with Drug B they may compete for the CYP3A enzyme
      • This competition may affect blood levels of either one or both of the drugs

  • CYP3A sensitive substrates

    • NOTE: These drugs are known to be significantly affected by CYP3A inhibitors/inducers
    • Albendazole (Albenza®) [5]
    • Alfentanil (Alfenta®) - drug has narrow therapeutic index [9]
    • Aliskiren (Tekturna®) [7]
    • Almotriptan (Axert®) [7]
    • Alprazolam (Xanax®) [7]
    • Amlodipine (Norvasc®) [5,7]
    • Aprepitant (Emend®) [9]
    • Aripiprazole (Abilify®) [7]
    • Avanafil (Stendra®) [7]
    • Brexpiprazole (Rexulti®) [7]
    • Bromocriptine (Cycloset®, Parlodel®) [7]
    • Budesonide (Entocort®, Pulmicort®) [9]
    • Buprenorphine (Suboxone®, Butrans®, etc.) [7]
    • Butorphanol (Stadol®) [7]
    • Buspirone (Buspar®) [9]
    • Cariprazine (Vraylar®) [7]
    • Clindamycin (Cleocin®) [7]
    • Clonazepam (Klonopin®) (probable) [7]
    • Colchicine (Colcrys®, Mitigare®) [7]
    • Conivaptan (Vaprisol®)  [9]
    • Cyclophosphamide (Cytoxan®)  [5]
    • Cyclosporine (Neoral®, Gengraf®, Sandimmune®) - drug has narrow therapeutic index [9]
    • Dabrafenib (Tafinlar®) [7]
    • Daclatasvir (Daklinza™) [7]
    • Darifenacin (Enablex®) [9]
    • Darunavir (Prezista®) [9]
    • Dasatinib (Sprycel®) [9]
    • Diazepam (Valium®) [5,7]
    • Dienogest (progesterone in oral contraceptives) [7]
    • Dihydroergotamine (DHE-45®, Migranal®) - drug has narrow therapeutic index [7,9]
    • Disopyramide (Norpace®) [5,7]
    • Dronedarone (Multaq®) [9]
    • Drospirenone (progesterone in oral contraceptives) [7]
    • Elbasvir (Zepatier®) [7]
    • Eletriptan (Relpax®) [7,9]
    • Enzalutamide (Xtandi®) [7]
    • Eplerenone (Inspra®) [7,9]
    • Ergotamine (Cafergot®) [7]
    • Eszopiclone (Lunesta®) [7]
    • Ethinyl Estradiol (oral contraceptives, Ortho Evra®, NuvaRing®) [7]
    • Etonogestrel (Implanon®, Nexplanon®, NuvaRing®) [7]
    • Everolimus (Afinitor®) [9]
    • Felodipine (Plendil®)  [9]
    • Fentanyl (Duragesic®) - drug has narrow therapeutic index [9]
    • Flibanserin (Addyi®) - major substrate [7]
    • Fluticasone (Flovent®, Arnuity Ellipta®) [7, 9]
    • Grazoprevir (Zepatier®) [7]
    • Guanfacine (Intuniv®) [7]
    • Hydrocodone (Norco®, Vicodin®, etc.) [7]
    • Iloperidone (Fanapt®) [7]
    • Indinavir (Crixivan®) [9]
    • Ivabradine (Corlanor®) [7]
    • Lapatinib (Tykerb®) [7]
    • Levomilnacipran (Fetzima®) [7]
    • Lopinavir and Ritonavir (Kaletra®) [9]
    • Lovastatin (Mevacor®) [9]
    • Lurasidone (Latuda®) [7, 9]
    • Maraviroc (Selzentry®) [9]
    • Medroxyprogesterone acetate (Depo-Provera®) [7]
    • Methadone [5]
    • Midazolam (Versed®) [9]
    • Mirtazapine (Remeron®) [7]
    • Naloxegol (Movantik®) [7]
    • Nevirapine (Viramune®) [7]
    • Nisoldipine (Sular®) [9]
    • Ospemifene (Osphena®) [7]
    • Oxycodone (Percocet®, Oxycontin®) [7]
    • Paritaprevir (Viekira Pak™, Technivie™) - major substrate [7]
    • Pimozide (Orap®) - drug has narrow therapeutic index [9]
    • Praziquantel (Biltricide®) [2,7]
    • Propafenone (Rythmol®) [7]
    • Quetiapine (Seroquel®) [7, 9]
    • Quinidine - drug has narrow therapeutic index [9]
    • Repaglinide (Prandin®) [7]
    • Roflumilast (Daliresp®) [7]
    • Salmeterol (Serevent®) [7]
    • Saquinavir (Invirase®) [9] 
    • Sildenafil (Viagra®) [9]
    • Simeprevir (Olysio®) [7]
    • Simvastatin (Zocor®) [9]
    • Sirolimus (Rapamune®) - drug has narrow therapeutic index [9]
    • Suvorexant (Belsomra®) [7]
    • Tacrolimus (Prograf®) - drug has narrow therapeutic index [9]
    • Tadalafil (Cialis®) [7]
    • Tamsulosin (Flomax®) [7]
    • Temsirolimus (Torisel®) [7]
    • Ticagrelor (Brilinta®) [7]
    • Tinidazole (Tindamax®) [7]
    • Tofacitinib (Xeljanz®) (major substrate) [7]
    • Tolvaptan (Samsca®) [9]
    • Tipranavir (Aptivus®) [9]
    • Triazolam (Halcion®) [9]
    • Vardenafil (Levitra®) [9]
    • Velpatasvir (Epclusa®) [7]
    • Verapamil (Calan®, Covera-HS®, Verelan®, etc) [7]
    • Vilanterol (Anoro Ellipta®) [7]
    • Vilazodone (Viibryd®) [7]
    • Vorapaxar (Zontivity®) [7]
    • Zolpidem (Ambien®) [7]

  • CYP3A substrates

    • Alcohol (ethanol) [3]
    • Alfuzosin (Uroxatral®) [7]
    • Amiodarone (Cordarone®) [5]
    • Apixaban (Eliquis®) [7]
    • Atorvastatin (Lipitor®) [7]
    • Beclomethasone (Qvar®) [7]
    • Boceprevir (Victrelis®) [7]
    • Canagliflozin (Invokana™) - minor substrate [7]
    • Carbamazepine (Tegretol®)  [2]
    • Ciclesonide (Alvesco®, Omnaris®) [7]
    • Cilostazol (Pletal®) [5]
    • Clarithromycin (Biaxin®) [5]
    • Clomipramine (Anafranil®) [11]
    • Clopidogrel (Plavix®) [7]
    • Clozapine (Clozaril®) [7]
    • Codeine [5]
    • Delavirdine (Rescriptor®) [7]
    • Desvenlafaxine (Pristiq®) - minor substrate [7]
    • Dexamethasone (DexPak®, Decadron®, etc) [5]
    • Dextromethorphan (multiple cough suppressants) [1]
    • Diltiazem (Cardizem®, Cartia®, etc) [5]
    • Doxazosin (Cardura, Cardura XL®) [7, for Cardura XL®]
    • Edoxaban (Savaysa®) - minor substrate [7]
    • Enalapril (Vasotec®) [5]
    • Erythromycin (E.E.S.®, Ery-Tab®, etc) [5]
    • Estradiol (Estrace®, Climara®, etc) [5]
    • Ethanol (beverage alcohol) [3]
    • Etonogestrel (Implanon®, Nexplanon® NuvaRing®) [7]
    • Felodipine (Plendil®) [5]
    • Fluvastatin (Lescol®) - minor substrate [7]
    • Flunisolide (Aerospan®) [7]
    • Glyburide (DiaBeta®) [6] [7]
    • Haloperidol (Haldol®) [5]
    • Hydrocortisone (Kenalog®, etc) [5]
    • Imipramine (Tofranil®) [11]
    • Indacaterol (Arcapta®) [7]
    • Indapamide [8]
    • Isosorbide dinitrate (Isordil®) [5]
    • Isosorbide mononitrate (ISMO®) [5]
    • Isotretinoin (Accutane®, Claravis®, etc.) (in vitro evidence only) [7]
    • Ivermectin (Stromectol®) - major substrate [7]
    • Linagliptin (Tradjenta®) [7]
    • Losartan (Cozaar®) [7]
    • Metaxalone (Skelaxin®) [7]
    • Mometasone (Asmanex®) [7]
    • Montelukast (Singulair®) (in vitro evidence only) [7]
    • Nateglinide (Starlix®) [7]
    • Nicardipine (Cardene®) [5]
    • Nifedipine (Adalat®, Procardia®, etc) [7]
    • Ondansetron (Zofran®) [5]
    • Oral contraceptives [7]
    • Paliperidone (Invega®) (in vitro evidence only) [7]
    • Pioglitazone (Actos®) [7]
    • Prasugrel (Effient®) [7]
    • Progesterone (Provera®, etc.) [5]
    • Quinidine [2,7]
    • Ramelteon (Rozerem®) (minor substrate) [7]
    • Rifabutin (Mycobutin®) [7]
    • Risperidone (Risperdal®) [7]
    • Rivaroxaban (Xarelto®) [5]
    • Saxagliptin (Onglyza®) [7]
    • Silodosin (Rapaflo®) [7]
    • Sertraline (Zoloft®) (minor substrate) [5]
    • Sitagliptin (Januvia®) [7]
    • Tamoxifen [7]
    • Telaprevir (Incivek®) [7]
    • Telithromycin (Ketek®) [7]
    • Terbinafine (Lamisil®) [7]
    • Testosterone (Androgel®, etc) [5]
    • Tiotropium (Spiriva®) (minor substrate) [7]
    • Tramadol (Ultram®) [7]
    • Trazodone [7]
    • Voriconazole (Vfend®) [7]
    • Voxilaprevir (Vosevi™) [7]
    • Zaleplon (Sonata®) (minor substrate) [7]
    • Zileuton (Zyflo®) [7]
    • Ziprasidone (Geodon®) [7]

  • 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 - SuperCYP website
  • 3 - PMID 9884161
  • 4 - PMID 12011477
  • 5 - PMID 18043468 - big 3a chart
  • 6 - PMID 21182938
  • 7 - Manufacturer's Package Insert (for drug labeled)
  • 8 - PMID 19074530
  • 9 - FDA drug development and drug interactions - CLICK HERE
  • 10 - PMID 15557548
  • 11 - PMID 17471183
  • 12 - PMID 18505790