P-gp Transport

P-gp is an ATP driven efflux pump encoded by the MDR1 gene, capable of transporting a wide spectrum of chemical structures as well as different classes of drugs.

Why is P-gp Transport Important?
Active transport by P-glycoprotein (P-gp) can represent a serious hurdle for pharmaceuticals as transport by P-gp has been associated with reduced bioavailability of orally administered drugs and with decreased ability of drug candidates to cross blood-tissue barriers such as the blood-brain barrier. In addition, if a drug is subject to significant P-gp efflux, its distribution, absorption and elimination could be altered by potent P-gp inhibitors. Evidence for drug-drug interactions due to inhibition of P-gp have been reported in human clinical studies. This is best documented for quinidine-digoxin interactions in which decreased renal and intestinal clearance of digoxin and increased plasma drug levels have been reported when quinidine is administered to patients taking digoxin. These changes have been attributed to inhibition of P-gp by quinidine where a significant portion of digoxin elimination is mediated by P-gp. Therefore, from the drug discovery and development perspective, knowledge of the transport of drug candidates by P-gp is desirable at an early stage of the drug design process.

P-gp Model
A database of 256 chemically diverse compounds with P-gp transport properties was assembled from the literature. The P-gp transport of each compound was assigned 'yes' if transported by the protein and 'no' if not transported. There is no single experimental method to conclusively identify a compound as a substrate for P-gp. Therefore, identification of the transport classification was based on at least two concurrent literature values from different assays, for example bi-directional Caco-2 measurements, ATPase activity or inhibition of transport of marker substrates. The model classifies molecules as likely to be substrates for P-gp (yes) or not likely (no).  The performance of this model was assessed on an independent test set of 51 compounds, of which 82% of the non-substrates and 79% of the substrates were correctly classified.

Observed vs Predicted P-gp Category