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- Please note
- 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.
- ACRONYMS AND DEFINITIONS
- CYP - Cytochrome P450
- CYP3A - includes both CYP3A4 and CYP3A5
- Substrate - a drug that is metabolized by a certain enzyme is a substrate of that enzyme
- CYTOCHROME P450
- Overview
- 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 (e.g. 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
- Inducers - CYP inducers increase the activity of CYP enzymes. This may increase the metabolism of other drugs that are substrates of the enzyme reducing their exposure.
- Inhibitors - CYP inhibitors reduce the activity of CYP enzymes. This may decrease the metabolism of other drugs that are substrates of the enzyme increasing their exposure.
- 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 while also inhibiting or inducing 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
- Compounding can also occur between CYP enzymes and cell transport systems (ex. p-glycoprotein, OAT, etc.)
- 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
- 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
- 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 (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
- 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]
- Pitolisant (Wakix®) [7]
- Prednisone [9]
- Rufinamide (Banzel®) [9]
- Topiramate (Topamax®) [7]
- CYP3A 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]
- CYP3A INHIBITORS
- CYP3A 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]
- 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]
- Letermovir (Prevymis®) [7]
- 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]
- Isradipine (Dynacirc®) [2,5]
- 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 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]
- 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]
- Zafirlukast (Accolate®) (in vitro data only) [7]
- CYP3A SUBSTRATES
- CYP3A sensitive substrates
- NOTE: These drugs are known to be significantly affected by CYP3A inhibitors and 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]
- Apremilast (Otezla®) [7]
- Aprepitant (Emend®) [9]
- Aripiprazole (Abilify®) [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]
- 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]
- Exemestane (Aromasin®) - may be affected by strong inducers [7]
- 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]
- Lefamulin (Xenleta™) [7]
- Lemborexant (Dayvigo®) [7]
- Levomilnacipran (Fetzima®) [7]
- Lopinavir and Ritonavir (Kaletra®) [9]
- Lovastatin (Mevacor®) [9]
- Lumateperone (Caplyta®) [7]
- 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]
- Rimegepant (Nurtec®) [7]
- Risperidone (Risperdal®) [7]
- Roflumilast (Daliresp®) [7]
- Salmeterol (Serevent®) [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]
- 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]
- Zonisamide (Zonegran™) [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]
- Cenobamate (Xcopri™) [7]
- 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]
- 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]
- Pioglitazone (Actos®) [7]
- Pitolisant (Wakix®) - minor substrate [7]
- Prasugrel (Effient®) [7]
- Progesterone (Provera®, etc.) [5]
- Ramelteon (Rozerem®) (minor substrate) [7]
- Rifabutin (Mycobutin®) [7]
- Rivaroxaban (Xarelto®) [5]
- 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]
- Upadacitinib (Rinvoq®) [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