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- ACRONYMS AND DEFINITIONS
- CYP - cytochrome P450
- CYP3A4/5 - cytochrome P450 3A4 and 3A5 share many of the same structural and metabolic properties, so they are considered collectively on this page
- Sensitive substrate - a drug whose exposure has been shown to be significantly altered by CYP3A4/5 inducers and/or inhibitors in studies. For other substrates, the clinical significance of inducer/inhibitor interactions is not as well-defined.
- NOT A COMPLETE LIST
- The information presented here is NOT A COMPLETE LIST of CYP3A4/5 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.
- CYTOCHROME P450
- Drug metabolism
- Cytochrome P450 (often abbreviated "CYP") is a class of liver enzymes involved in the metabolism of many medications. CYP enzymes are divided into subtypes (e.g. 2D6, 3A4, 2C8) based on their structure.
- Drugs may be metabolized by one or several different CYP enzymes. In some cases, one CYP enzyme is responsible for a majority of the drug's metabolism (major pathway), while other CYP enzymes contribute a small amount (minor pathway). Some drugs undergo no CYP metabolism, and some require CYP metabolism to become active. For example, clopidogrel (Plavix) has no antiplatelet effect until it is converted to its active metabolite by CYP2C19.
- CYP drug interactions
- Inducers and Inhibitors
- Inducers - CYP inducers increase enzyme activity and may decrease exposure to substrates
- Inhibitors - CYP inhibitors reduce enzyme activity and may increase exposure to substrates
- Certain chemicals and foods (e.g. tobacco smoke, grapefruit juice) may also act as CYP inducers and inhibitors
- One drug may inhibit or induce multiple enzymes and transporters (e.g. p-glycoprotein, OAT)
- Drugs may inhibit or induce the same enzyme they are metabolized by
- Inducers and inhibitors can be subdivided into strong, moderate, or weak depending on the degree of their effect
- 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
- Genetic factors
- Genetic differences in the genes that code for CYP enzymes can lead to variations in their activity. Patients with alleles that increase enzyme activity are referred to as "rapid metabolizers," and those with suppressive alleles are called "poor metabolizers." People in the middle are called "intermediate" or "normal" metabolizers.
- 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-defined while others are not
- Factors that can make drug interactions challenging
- New drugs
- During drug development, the FDA requires interaction testing with medications that are known to have significant effects on CYP enzymes and transporters. Obviously, there is no way to test a new drug with every medication available, meaning most drugs come to market with incomplete interaction profiles. After the medication is prescribed to a large number of people, other drug interactions are inevitably discovered.
- Research
- Drug research often occurs in a laboratory setting (in vitro) with animals and cell cultures. Findings from these experiments do not always reflect what happens in the human body (in vivo).
- Evolving information
- Drug metabolism is an evolving field, and researchers are just beginning to understand all the different ways the body eliminates medications. Cytochrome P450 enzymes have been studied for a while, but cell transport systems (e.g. p-glycoprotein, OAT) are a relatively new area of pharmacology, and their role in drug elimination has not been completely elucidated.
- 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 clinically significant, and patients should consult their healthcare provider if they are concerned about a possible interaction
- Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- CYP3A4/5 INDUCERS
- CYP3A4/5 strong inducers
- Carbamazepine (Tegretol®) [9]
- Enzalutamide (Xtandi®) [7]
- Phenobarbital [5]
- Phenytoin (Dilantin®) [9]
- Rifampin [9]
- St. John's Wort [9]
- CYP3A4/5 moderate inducers
- Bosentan (Tracleer®) [9]
- Efavirenz (Sustiva®) [9]
- Etravirine (Intelence®) [9]
- Modafinil (Provigil®) [9]
- Nafcillin [9]
- CYP3A4/5 weak inducers
- Aprepitant (Emend®) [9]
- Armodafinil (Nuvigil®) [9]
- Clobazam (Onfi®) [7]
- Delafloxacin (Baxdela®) [7]
- Echinacea [9]
- Lesinurad (Zurampic®) [7]
- Pioglitazone (Actos®) [9]
- Pitolisant (Wakix®) [7]
- Prednisone [9]
- Rufinamide (Banzel®) [9]
- Topiramate (Topamax®) [7]
- CYP3A4/5 inducers (class not well-defined)
- Cenobamate (Xcopri™) [7]
- Dabrafenib (Tafinlar®) [7]
- Dexamethasone (Decadron®) [7]
- Eslicarbazepine (Aptiom®) [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]
- CYP3A4/5 INHIBITORS
- CYP3A4/5 strong inhibitors
- Boceprevir (Victrelis®) [7,9]
- Clarithromycin (Biaxin®) [1,9]
- Cobicistat (part of Stribild®) [7]
- Conivaptan (Vaprisol®) [9]
- Danazol [13]
- 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]
- CYP3A4/5 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]
- Letermovir (Prevymis®) [7]
- Verapamil (Calan®, Covera-HS®, Verelan®, etc) [9]
- CYP3A4/5 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]
- Isradipine (Dynacirc®) [2,5]
- Isoniazid [9]
- Ivacaftor (Kalydeco®) [7]
- Lapatinib (Tykerb®) [7]
- Nilotinib (Tasigna®) [9]
- Oral contraceptives [9]
- Pibrentasvir (Mavyret™) [7]
- Ranitidine (Zantac®) [9]
- Ranolazine (Ranexa®) [9]
- Tipranavir (Aptivus®) [9]
- Viloxazine (Qelbree®) [7]
- Zileuton (Zyflo®) [9]
- CYP3A4/5 inhibitors (class not well-defined)
- Azithromycin (Zithromax®) [5]
- Bromocriptine (Cycloset®, Parlodel®) [7]
- Cenobamate (Xcopri™) [7]
- Chloramphenicol [2]
- Delavirdine (Rescriptor®) [7]
- Desipramine (Norpramin ®) [5]
- Danazol [5]
- Felodipine (Plendil®) [5]
- Ibrexafungerp (Brexafemme®) (in vitro) [7]
- Iloperidone (Fanapt®) - in vitro studies only [7]
- Lefamulin (Xenleta™) [7]
- Linagliptin (Tradjenta®) [7]
- Nicardipine (Cardene®) [5]
- Nifedipine (Adalat®, Procardia®, etc) [7]
- Quinidine [5]
- Simeprevir (Olysio®) - intestinal CYP3A4 inhibitor [7]
- Spironolactone (Aldactone®) - irreversible inhibitor in vitro [7]
- Zafirlukast (Accolate®) (in vitro data only) [7]
- CYP3A4/5 SUBSTRATES
- CYP3A4/5 sensitive substrates
- NOTE: A sensitive substrate is a drug whose exposure has been shown to be significantly altered by CYP3A4/5 inducers and/or inhibitors in studies
- Albendazole (Albenza®) [5]
- Alfentanil (Alfenta®) - drug has narrow therapeutic index [9]
- Aliskiren (Tekturna®) [7]
- Almotriptan (Axert®) [7]
- Alprazolam (Xanax®) [7]
- Amlodipine (Norvasc®) [5,7]
- Apremilast (Otezla®) [7]
- Aprepitant (Emend®) [9]
- Aripiprazole (Abilify®) [7]
- Atogepant (Qulipta®) [7]
- Avanafil (Stendra®) [7]
- Benzhydrocodone (Apadaz®) [7]
- Brexpiprazole (Rexulti®) [7]
- Bromocriptine (Cycloset®, Parlodel®) [7]
- Budesonide (Entocort®, Pulmicort®) [9]
- Buprenorphine (Suboxone®, Butrans®, etc.) [7]
- Butorphanol (Stadol®) [7]
- Buspirone (Buspar®) [9]
- Cannabidiol (Epidiolex®) [7]
- Cariprazine (Vraylar®) [7]
- Cilostazol (Pletal®) [7]
- Clindamycin (Cleocin®) [7]
- Clonazepam (Klonopin®) (probable) [7]
- Codeine [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]
- Daridorexant (Quviviq®) [7]
- Darifenacin (Enablex®) [9]
- Darunavir (Prezista®) [9]
- Dasatinib (Sprycel®) [9]
- Dexlansoprazole (Dexilant®) [7]
- Diazepam (Valium®) [5,7]
- Dienogest (progesterone in oral contraceptives) [7]
- Dihydrocodeine (Trezix®) [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]
- Esomeprazole (Nexium®) [7]
- Eszopiclone (Lunesta®) [7]
- Ethinyl Estradiol (oral contraceptives, Ortho Evra®, NuvaRing®) [7]
- Etonogestrel (Implanon®, Nexplanon®, NuvaRing®) [7]
- Everolimus (Afinitor®) [9]
- Exemestane (Aromasin®) - may be affected by strong inducers [7]
- Felodipine (Plendil®) [9]
- Fentanyl (Duragesic®) - drug has narrow therapeutic index [9]
- Finerenone (Kerendia®) - major substrate [7]
- Flibanserin (Addyi®) - major substrate [7]
- Fluticasone (Flovent®, Arnuity Ellipta®) [7, 9]
- Grazoprevir (Zepatier®) [7]
- Guanfacine (Intuniv®) [7]
- Hydrocodone (Norco®, Vicodin®, etc.) [7]
- Ibrexafungerp (Brexafemme®) [7]
- Iloperidone (Fanapt®) [7]
- Ibrutinib (Imbruvica®) [7]
- Indinavir (Crixivan®) [9]
- Ivabradine (Corlanor®) [7]
- Ivacaftor (Kalydeco®) [7]
- Lapatinib (Tykerb®) [7]
- Lansoprazole (Prevacid®) [7]
- Lefamulin (Xenleta™) [7]
- Lemborexant (Dayvigo®) [7]
- Levomilnacipran (Fetzima®) [7]
- Lomitapide (Juxtapid®) [7]
- Lopinavir and Ritonavir (Kaletra®) [9]
- Lovastatin (Mevacor®) [9]
- Lumateperone (Caplyta®) [7]
- Lurasidone (Latuda®) [7, 9]
- Maraviroc (Selzentry®) [9]
- Medroxyprogesterone acetate (Depo-Provera®) [7]
- Meperidine (Demerol®) [7]
- Methadone [5]
- Midazolam (Versed®) [9]
- Mirtazapine (Remeron®) [7]
- Naldemedine (Symproic®) [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]
- Rimegepant (Nurtec®) [7]
- Risperidone (Risperdal®) [7]
- Roflumilast (Daliresp®) [7]
- Salmeterol (Serevent®) [7]
- Samidorphan (Lybalvi®) [7]
- Saquinavir (Invirase®) [9]
- Saxagliptin (Onglyza®) [7]
- 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]
- Tasimelteon (Hetlioz®) [7]
- Temsirolimus (Torisel®) [7]
- Ticagrelor (Brilinta®) [7]
- Tinidazole (Tindamax®) [7]
- Tipranavir (Aptivus®) [9]
- Tofacitinib (Xeljanz®) - major substrate [7]
- Tolvaptan (Samsca®) [9]
- Tramadol (Ultram®) [7]
- Trazodone (Desyrel®) [7]
- Triazolam (Halcion®) [9]
- Upadacitinib (Rinvoq®) [7]
- 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]
- Zonisamide (Zonegran™) [7]
- CYP3A4/5 substrates
- NOTE: Compared to sensitive substrates, the clinical significance of inducer/inhibitor interactions with these drugs is not as well-defined
- Abrocitinib (Cibinqo®) - minor substrate [7]
- 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]
- Cenobamate (Xcopri™) [7]
- Ciclesonide (Alvesco®, Omnaris®) [7]
- Clarithromycin (Biaxin®) [5]
- Clomipramine (Anafranil®) [11]
- Clopidogrel (Plavix®) [7]
- Clozapine (Clozaril®) [7]
- Delavirdine (Rescriptor®) [7]
- Desvenlafaxine (Pristiq®) - minor substrate [7]
- Dexamethasone (DexPak®, Decadron®, etc) [5]
- Dextromethorphan (multiple cough suppressants) [1]
- Diltiazem (Cardizem®, Cartia®, etc) [5]
- Dolutegravir (Tivicay®) [7]
- Doxazosin (Cardura, Cardura XL®) [7, for Cardura XL®]
- Dutasteride (Avodart®) [7]
- 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]
- Finasteride (Propecia®, Proscar®) [7]
- 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]
- Isradipine (Dynacirc®) [2,5]
- Ivermectin (Stromectol®) - major substrate [7]
- Lacosamide (Vimpat®) [7]
- Letermovir (Prevymis®) [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]
- Ozanimod (Zeposia®) [7]
- Paliperidone (Invega®) - in vitro evidence only [7]
- Pantoprazole (Protonix®) - minor substrate [7]
- Pioglitazone (Actos®) [7]
- Pitolisant (Wakix®) - minor substrate [7]
- Prasugrel (Effient®) [7]
- Progesterone (Provera®, etc.) [5]
- Rabeprazole (Aciphex®) [7]
- Ramelteon (Rozerem®) - minor substrate [7]
- Rifabutin (Mycobutin®) [7]
- Rivaroxaban (Xarelto®) [5]
- Silodosin (Rapaflo®) [7]
- Sertraline (Zoloft®) - minor substrate [5]
- Sitagliptin (Januvia®) [7]
- Spironolactone (Aldactone®) - major substrate [7]
- Tamoxifen [7]
- Telaprevir (Incivek®) [7]
- Telithromycin (Ketek®) [7]
- Terbinafine (Lamisil®) [7]
- Testosterone (Androgel®, etc) [5]
- Tiotropium (Spiriva®) - minor substrate [7]
- Venlafaxine (Effexor®) - minor substrate [7]
- Voriconazole (Vfend®) [7]
- Voxilaprevir (Vosevi™) [7]
- Zaleplon (Sonata®) - minor substrate [7]
- Zileuton (Zyflo®) [7]
- Ziprasidone (Geodon®) [7]
- 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 - 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
- 13 - Zocor PI