P-gp efflux pump

Although nucleoside analogs are not substrates for P-gp or CYP3A4, most protease inhibitors and NNl are substrates for both the P-gp efflux pump (Aungst 1999 ... 

The use of Caco-2 cell monolayers has gained in popularity as an in vivo human absorption surrogate moreover, the monolayers are generally accepted as a primary absorption screening tool by several pharmaceutical companies [10]. However, Caco-2 cell permeability measurements exhibit certain limitations due to the mechanisms involved. Both passive and active pathways exist active transport tends to increase the absorption across the cells and, since Caco-2 cells overexpress the P-glycoprotein (P-gp) efflux pump, the absorption of some compounds across these cells may be underestimated. 

Whereas some transporters located in the apical wall of the enterocyte facilitate absorption, there are others that serve as efflux transporters. These are considered as the multiple drug resistance (MDR) transporters, and they play a major role in the disposition of many drugs. The most extensively studied MDR transporter is the apical P-glycoprotein (P-gp) efflux pump that reduces the fraction of drug absorbed by transporting the drug from the enterocyte back to the intestinal lumen [6]. 

Approaches to stabilize or avoid instability Prodrugs Enteric coating (protection in stomach) Lipid vehicles (micelles or emulsions/microemulsions) Enzyme inhibitor Lymphatic delivery (to avoid first-pass metabolism) Lipid prodrugs P-gp efflux pump inhibitors ... 

Given that the P-gp efflux pump and CYP3A share a large number of substrates, what is the effect of administrating a P-gp inhibitor on liver and gut metabolism ... 

Interestingly, the aforesaid metabolites a) and (b) essentially retain only about 33% of the pharmacological activity in comparison to that of quinidine. Furthermore, it has been observed that the quinidine, which being a P-gp substrate, invariably checks the renal tubular seeretion of digoxin via the P-gp efflux pump route, thereby giving rise to an enhanced plasma concentration for digoxin. 

Inhibition of the P-glycoprotein (P-gp) efflux pump, which is responsible for secretion of the absorbed molecules entering the enterocytes back to the gastrointestinal lumen. The P-gp activity can be inhibited by some pharmaceutical excipients like polyethylene glycol. Tween 80, and Cre-mophor EL [105]. Accordingly, incorporation of any of these excipients into the ME components can increase the bioavailability for drugs, which are known substrates of P-gp efflux pumps. 

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

P-gp) play an active role, and some of these function quite effectively as efflux pumps. One can, therefore, envisage a situation where brain efflux of the pyridinium intermediate competes with in situ activation by hydrolysis. 

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