P-glycoprotein

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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 is also referred to as "Multidrug Resistance Protein (MDR1)," and by its gene name, "ABCB1"
P-glycoprotein 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
P-glycoprotein transports medications (often after they are metabolized) out of a cell (efflux) so that they can be eliminated from the body

Illustration of p-glycoprotein activity

P-glycoprotein is found in cells of the intestine, kidney, liver, and blood-brain barrier

Intestines - p-glycoprotein limits drug absorption from the intestine
Liver - p-glycoprotein transports medications into the bile for excretion from the body
Kidney - p-glycoprotein transports medications into the urine for excretion from the body
Blood-brain barrier - p-glycoprotein keeps 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]
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

P-GLYCOPROTEIN