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- Please note
- The information presented here is NOT A COMPLETE LIST of P-glycoprotein 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
- P-gp - P-glycoprotein
- Substrate - a drug that is metabolized by a certain enzyme is a substrate of that enzyme
- P-GLYCOPROTEIN (PERMEABILITY GLYCOPROTEIN)
- Overview
- P-glycoprotein, also referred to as multidrug resistance protein (MDR1) and its gene name ABCB1, is a member of a class of transport molecules called ATP-binding cassette transporters or ABC transporters for short
- P-glycoprotein is located in the cell membrane of various tissues, where it transports medications, often after they are metabolized, out of a cell so that they can be eliminated from the body
- Depending on the tissue, P-glycoprotein has the following actions:
- Intestines - limits drug absorption from the intestine
- Liver - transports medications into the bile for excretion from the body
- Kidney - transports medications into the urine for excretion from the body
- Blood-brain barrier - prevents medications from entering the central nervous system [3]
- P-glycoprotein drug interactions
- Inducers and Inhibitors
- Inducers - increase the activity of p-glycoprotein
- Inhibitors - block the action of p-glycoprotein
- When p-glycoprotein inducers or inhibitors are taken with other medications that are transported by p-glycoprotein, they can alter the elimination of that medication
- Drugs may be transported by p-glycoprotein and also inhibit or induce it 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 p-glycoprotein
- Competitive inhibition
- If two drugs are transported by p-glycoprotein, they may "compete" for it, and this can alter the elimination 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 it is transported by p-glycoprotein
- Drug B inhibits CYP2D6. Drug C inhibits p-glycoprotein.
- 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
- P-glycoprotein is coded for by a gene called ABCB1
- Since individuals vary in their genetic makeup, their ABCB1 gene can vary also
- Some people have ABCB1 genes that produce p-glycoprotein transporters that are less effective
- Gene variations in the ABCB1 gene can affect how an individual eliminates 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
- P-GLYCOPROTEIN INDUCERS
- P-glycoprotein inducers
- Carbamazepine (Tegretol®) [1]
- Clotrimazole (Mycelex®) [3]
- Dexamethasone (Decadron®) [3]
- Fosamprenavir (Lexiva®) [6]
- Indinavir (Crixivan®) [3]
- Morphine (MS Contin®, etc.) [3]
- Nelfinavir (Viracept®) [3]
- Phenobarbital [4]
- Phenothiazines (ex. promethazine, trifluoperazine) [3]
- Phenytoin (Dilantin®) [1]
- Prazosin (Minipress®) [4]
- Retinoic acid [3]
- Rifampin [1]
- Ritonavir (Norvir®) [1,3]
- Saquinavir (Invirase®) [3]
- Spironolactone (Aldactone®) [8]
- St. John's Wort [1]
- Tipranavir (Aptivus®) [1]
- P-GLYCOPROTEIN INHIBITORS
- P-glycoprotein inhibitors
- Abrocitinib (Cibinqo®) [6]
- Amiodarone (Cordarone®) [4]
- Atorvastatin (Lipitor®) [3]
- Azithromycin (Zithromax®) [1]
- Boceprevir (Victrelis®) - Drug PI states possible inhibitor [6]
- Bromocriptine (Cycloset®, Parlodel®, etc.)
- Cannabidiol (Epidiolex®) [6]
- Captopril (Capoten®) [1]
- Carvedilol (Coreg®) [1,3]
- Clarithromycin (Biaxin®) [2]
- Cobicistat (part of Stribild®) [6]
- Conivaptan (Vaprisol®) [1]
- Cyclosporine (Neoral®, Gengraf®, Sandimmune®) [1]
- Daclatasvir (Daklinza™) [6]
- Diltiazem (Cardizem®, Cartia®, Dilacor®, Diltia®) [1,4]
- Doxazosin (Cardura®) [4,9]
- Dronedarone (Multaq®) [1]
- Erythromycin (E.E.S®, Ery-tab®) [1]
- Felodipine (Plendil®) [1]
- Fluvastatin (Lescol®) [4]
- Glecaprevir (Mavyret™) [6]
- Ibrexafungerp (Brexafemme®) [in vitro] [6]
- Indinavir (Crixivan®) [1]
- Itraconazole (Sporanox®) [1]
- Ivacaftor (Kalydeco®) [6]
- Ketoconazole (Nizoral®) [1]
- Lapatinib (Tykerb®) [6]
- Ledipasvir (Harvoni™) [6]
- Letermovir (Prevymis®) [6]
- Linagliptin (Tradjenta®) [6]
- Lomitapide (Juxtapid®) [6]
- Lopinavir and ritonavir (Kaletra®) [1]
- Lovastatin (Mevacor®) [4]
- Meperidine (Demerol®) [3]
- Methadone [3]
- Nelfinavir (Viracept®) [1]
- Nicardipine (Cardene®) [4,5]
- Paritaprevir (Viekira Pak™, Technivie™) [6]
- Pentazocine (Talwin®) [3]
- Pibrentasvir (Mavyret™) [6]
- Progesterone [3]
- Quercetin (supplement) [1]
- Quinidine [1]
- Ranolazine (Ranexa®) [1]
- Reserpine [1]
- Ritonavir (Norvir®) [1]
- Saquinavir (Invirase®) [1]
- Sarecycline (Seysara™)
- Simeprevir (Olysio®) [6]
- Simvastatin (Zocor®) [4]
- Suvorexant (Belsomra®) [in vitro data] [6]
- Tacrolimus (Prograf®) [1]
- Tamoxifen [3]
- Telaprevir (Incivek®) [6]
- Ticagrelor (Brilinta®) [6]
- Vardenafil (Levitra®) [in vitro data] [6]
- Velpatasvir (Epclusa®) [6]
- Verapamil (Calan®,Covera-HS®, Isoptin®, Verelan®) [1]
- Voclosporin (Lupkynis®) [6]
- Vorapaxar (Zontivity®) (weak inhibitor) [6]
- Voxilaprevir (Vosevi™) [6]
- Zonisamide (Zonegran™) (weak inhibitor) [6]
- DRUGS TRANSPORTED BY P-GLYCOPROTEIN (SUBSTRATES)
- P-glycoprotein substrates
- Aliskiren (Tekturna®) [1,6]
- Ambrisentan (Letairis®) [1]
- Apixaban (Eliquis®) [6]
- Apremilast (Otezla®) [6]
- Atogepant (Qulipta®) [6]
- Atorvastatin (Lipitor®) [4]
- Betrixaban (Bevyxxa®) [6]
- Boceprevir (Victrelis®) [6]
- Bromocriptine (Cycloset®, Parlodel®) [4,10]
- Cannabidiol (Epidiolex®) [6]
- Carbamazepine (Tegretol®) [4]
- Carvedilol (Coreg®) [4]
- Cimetidine (Tagamet®) [3]
- Cladribine (Mavenclad®) [6]
- Colchicine (Colcrys®, Mitigare®) [1,6]
- Cyclosporine (Neoral®, Gengraf®, Sandimmune®) [2]
- Dabigatran (Pradaxa®) [1]
- Daclatasvir (Daklinza™) [6]
- Dapagliflozin (Farxiga®) - weak substrate [6]
- Dasabuvir (Viekira Pak™) [6]
- Delafloxacin (Baxdela™) [in vitro data] [6]
- Dexamethasone (Decadron®) [3]
- Digoxin (Lanoxin®) [1]
- Diltiazem (Cardizem®, Cartia®, Dilacor®, Diltia®) [3]
- Dolutegravir (Tivicay®) [6]
- Domperidone [3]
- Doxorubicin (Adriamycin®) [3]
- Edoxaban (Savaysa®) [6]
- Elbasvir (Zepatier®) [6]
- Empagliflozin (Jardiance®) [6]
- Empagliflozin (Jardiance®) [6]
- Ertugliflozin (Steglatro™) [6]
- Erythromycin (E.E.S®, Ery-tab®) [3]
- Estradiol (Climara®, Estrace®, etc.) [3]
- Etoposide (Toposar®) [3]
- Everolimus (Afinitor®) [1]
- Ezetimibe (Zetia®) [7]
- Fexofenadine (Allegra®) [1]
- Fidaxomicin (Dificid®) [6]
- Fluvastatin (Lescol®) [4]
- Fosamprenavir (Lexiva®) [6]
- Glecaprevir (Mavyret™) [6]
- Grazoprevir (Zepatier®) [6]
- Ibrexafungerp (Brexafemme®) [6]
- Imatinib (Gleevec®) [1]
- Indacaterol (Arcapta®) (minor substrate) [6]
- Indinavir (Crixivan®) [1]
- Itraconazole (Sporanox®) [3]
- Ivermectin (Stromectol®) [3]
- Lasmiditan (Reyvow®) (in vitro data) [6]
- Lapatinib (Tykerb®) [1,6]
- Ledipasvir (Harvoni™) [6]
- Lefamulin (Xenleta™) [6]
- Letermovir (Prevymis®) [6]
- Levomilnacipran (Fetzima®) (weak substrate) [6]
- Linagliptin (Tradjenta®) [6]
- Loperamide (Imodium®) [2]
- Losartan (Cozaar®) [4]
- Lovastatin (Mevacor®) [4]
- Maraviroc (Selzentry®) [1]
- Methylprednisolone (Solu-Medrol®) [3]
- Methotrexate [2]
- Morphine (MS Contin®, etc.) [3]
- Naldemedine (Symproic®) [6]
- Nelfinavir (Viracept®) [3]
- Nilotinib (Tasigna®) [1]
- Ombitasvir (Viekira Pak™, Technivie™) [6]
- Paclitaxel (Taxol®) [1]
- Paliperidone (Invega®) [6]
- Paritaprevir (Viekira Pak™, Technivie™) [6]
- Phenytoin (Dilantin®) [4]
- Pibrentasvir (Mavyret™) [6]
- Posaconazole (Noxafil®) [1]
- Pravastatin (Pravachol®) [4]
- Prazosin (Minipress®) [4]
- Quinidine [3]
- Ranitidine (Zantac®) [3]
- Ranolazine (Ranexa®) [1]
- Rifaximin (Xifaxan®) [6]
- Rimegepant (Nurtec®) [6]
- Risperidone (Risperdal®) [6]
- Ritonavir (Norvir®) [1]
- Rivaroxaban (Xarelto®) [6]
- Saquinavir (Invirase®) [3]
- Saxagliptin (Onglyza®) [1,6]
- Silodosin (Rapaflo®) [6]
- Simvastatin (Zocor®) [4]
- Sirolimus (Rapamune®) [1]
- Sitagliptin (Januvia®) [1,6]
- Sofosbuvir (Sovaldi®) [6]
- Tacrolimus (Prograf®) [2]
- Ticagrelor (Brilinta®) [6]
- Telaprevir (Incivek®) [6]
- Tenofovir alafenamide (Descovy®) [6]
- Tetracycline [3]
- Tipranavir (Aptivus®) [6]
- Tolvaptan (Samsca®) [1]
- Topotecan (Hycamtin®) [1]
- Umeclidinium (Anoro Ellipta®) [6]
- Vecuronium [1]
- Velpatasvir (Epclusa®) [6]
- Verapamil (Calan®,Covera-HS®, Isoptin®, Verelan®) [3]
- Vilanterol (Anoro Ellipta®) [6]
- Vinblastine [3]
- Vincristine (Vincasar®) [1]
- Voxilaprevir (Vosevi™) [6]
- BIBLIOGRAPHY
- 1- FDA Drug Development and Drug Interactions. CLICK HERE
- 2 - PMID 17766652
- 3 - PMID 11996011
- 4 - PMID 18043468
- 5 - PMID 11145223
- 6 - Manufacturer's package insert (for labeled drug)
- 7 - PMID 16513445
- 8 - PMID 16740618
- 9 - PMID 19806783
- 10 - PMID 16263253