Permeability Glycoprotein 1 (P-gp, MDR1, ABCB1)

P-glycoprotein 1 (P-gp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1)

P-gp:  What and Where

Permeability glycoprotein 1 (P-gp) is the well-known member of the ABC superfamily of efflux transporter proteins. P-gp (aka MDR1, ABCB1, CD243; gene: ABCB1) is, by far, the most well-characterized of all the transporter proteins. P-gp has been shown to be ubiquitously expressed throughout the body, including on the luminal membrane surfaces of the gastrointestinal tract and blood-brain barrier, and on apical membranes of the liver and kidneys. Within these tissues, it plays a role in the efflux (i.e. extrusion) of a wide range of endogenous and exogenous compounds across biological membranes. P-gp expression and function in the intestines and the liver can play a dramatic role in drug absorption and clearance, respectively.                                  

P-gp Clinical Importance

P-gp was, and, continues to be indicted as playing a role in serious transporter-based drug-drug interactions. The clinical effect of a P-gp interaction varies depending on the site of interaction. In the case of the intestinal epithelia and the blood-brain barrier, P-gp can act as a barrier to absorption and distribution into the tissue; whereas in the liver or kidney, P-gp functions in biliary or renal excretion, respectively. Thus, a compound that interacts with P-gp, either as a substrate or an inhibitor, can be subject to or the cause of in a number of remarkable drug-drug interactions.

P-gp Regulatory Significance

Since its first appearance in the 2006 FDA draft guidance, regulatory agencies remain clear on the need for in vitro assessment of potential P-gp interaction for an NCE– it is a must. According to both the European Medicines Agency (EMA) Guideline on the Investigation of Drug Interactions(effective: January 2013) and the US Food and Drug Administration (FDA) Guidance to the Industry: Drug Interaction Studies (issued: Feb 2012), “all investigational drugs should be evaluated in vitro to determine whether they are a potential substrate.”2 A similar point of view is held for inhibitor assessment, which both agencies says is “recommended”3, mainly due to frequent concomitantly dosing with commonly prescribed drugs, such as digoxin.2

P-gp Clinically Relevant Probe Substrates and Inhibitors

Substrates, Inhibitors
aliskiren, amiodarone
ambrisentan, azithromycin
colchicine, captropril
dabigantran, carvediol
digoxin*, clarithomycin
everolimus, conivaptan
fexofenadine, cyclosporine‡
imatinib, diltiazem
lapatinib, droneddarone
maraviroc, erythromycine
nilotinib, fileodipine
posaconazole, itraconazole
ranolazine, ketoconazole‡
sazagliptin, quercetin
sirolimus, quinidine
sitagliptin, ranolazine
talinolol, ticagrelor
tolvaptan, valspordar‡
topotecan, verapamil‡

P-gp In Vitro Model

Caco-2 (clone: C2BbE1)

Characteristics, Benefits
P-gp natively expressed, No overexpression or selection needed
Complement of transporters, Uncover residual transporter interaction
Resemblance to tissue type (human intestinal epithelia4), Improved correlation to clinical outcome (absorption interactions)

MDR1-MDCK

Characteristics, Benefits
Overexpression, Increased sensitivity
hP-gp stably transfected into MDCK, Single transporter interaction
Model for tissue type (blood-brain barrier5), Improved correlation to clinical outcome (disposition interactions)

References
1. Giacomini KM, et al. (2010) Membrane transporters in drug development. Nature Reviews Drug Disc. 9(3):215-236
2. US Food and Drug Administration (Feb 2012) Draft Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing and Labeling Recommendations
3. European Medicines Agency (Jun 2012) Guideline on the Investigation of Drug Interactions
4. Hidalgo I, et al. (1989) Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 96(3): 736-49
5. Wang Q, et al. (2004) Evaluation of MDR-MDCK cell line as a permeability screen for the blood-brain barrier. Int J Pharm 20;288(2): 349-59