P-glycoprotein Inhibition

P-gp inhibition is in our portfolio of in vitro drug transporter services. Cyprotex delivers consistent, high quality data in line with our published transporter strategy review, for either your early stage screening projects or your later stage regulatory studies according to FDA, EMA, PMDA and ICH guidance.

The impact of P-glycoprotein inhibition and its measurement in vitro:

• P-gp is one of the most well-recognized efflux transporters in many tissues including the gastrointestinal tract, brain endothelium and kidney¹.
• Inhibition of P-gp has shown to be responsible for several clinical drug-drug interactions. For example, clarithromycin can inhibit the transport of the P-gp substrate digoxin resulting in a clinically significant elevation of plasma exposure and a decrease in renal clearance².
• The International Transporter Consortium¹, the FDA guidance³ and the EMA guideline⁴ recommend investigating inhibition of P-gp due to P-gp’s clinical importance in the absorption and disposition of substrate drugs.
• Cyprotex uses polarized Caco‑2 cell monolayers (the "gold-standard" methodology) to identify P-gp inhibitors using a range of test inhibitor concentrations in the presence of the clinically relevant probe substrate digoxin. This method conforms with the recommended methods within the International Transporter Consortium white paper¹, the FDA drug interactions guidance³ and the EMA drug interactions guideline⁴.
• However, if a test compound has inherently low passive permeability, then P-gp-expressing inside-out membrane vesicles can be used as an alternate in vitro test system to identify P-gp inhibitors and reduce the potential risk of false negatives from the polarized cell monolayer system for such compounds.

A set of known P-gp inhibitors were investigated in Cyprotex's Cellular P-gp inhibition assay using digoxin as substrate.

A set of known P-gp inhibitors were investigated in Cyprotex's Vesicle P-gp inhibition assay using N‑methyl‑quinidine as substrate.

_{1) The International Transporter Consortium (2010) Membrane transporters in drug development. Nat Rev Drug Disc 9(3); 215–236
2) Wakasugi H et al. (1998) Effect of clarithromycin on renal excretion of digoxin: Interaction with P-glycoprotein. Clin Pharmacol Ther 64(1); 123 -128
3) FDA Guidance for Industry – In Vitro Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions (January 2020)
4) The European Medicines Agency (EMA) Guideline on the Investigation of Drug Interactions (Adopted 2012)}