What is the mechanism of P-glycoprotein?
What is the mechanism of P-glycoprotein?
Human P-glycoprotein (ABCB1) is a primary multidrug transporter located in plasma membranes, that, utilizes the energy of ATP hydrolysis to pump toxic xenobiotics out of cells. P-glycoprotein employs a most unusual molecular mechanism to perform this drug transport function.
Is P-glycoprotein an active transporter?
P-glycoprotein (P-gp) is an ATP-binding cassette (ABC) transporter responsible for the multidrug resistance (MDR) phenotype when overproduced in the plasma membrane of tumor cells (1). In the absence of any known transport substrate, P-gp exhibits a basal ATPase activity, which is unusual for an active transporter (3).
What is the clinical relevance of P-glycoprotein P-gp )?
The drug efflux transporter P-glycoprotein (P-gp) is known to confer multidrug resistance in cancer chemotherapy. Because of its expression and localization, it has been suggested that P-gp plays an important role in cancer chemotherapy, intestinal absorption, and brain uptake.
How does P-glycoprotein work in intestine?
In the GI tract, P-gp is located on the apical surface of the mature epithelial cells and acts as a pump that transports drugs back into the GI lumen as they are absorbed across the intestinal mucosa.
What is a P-glycoprotein substrate?
Efflux transporters such as P-glycoprotein play an important role in drug transport in many organs. Important substrates of P-glycoprotein include calcium channel blockers, cyclosporin, dabigatran etexilate, digoxin, erythromycin, loperamide, protease inhibitors and tacrolimus.
What is expression of P-glycoprotein?
Expression of Pgp in the brain is an evolutionary step to protect the sensitive tissue against potential toxins. On the other hand, however, Pgp limits drug transport to brain for CNS acting drugs and, therefore, reduces their pharmacotherapeutic effectiveness.
Does azithromycin inhibit P-glycoprotein?
Macrolides: Erythromycin, Azithromycin, and Clarithromycin The FDA approved macrolide antibiotics (erythromycin, azithromycin, and clarithromycin) were all reported as p-gp inhibitors. This has been supported by many studies in the literature (64–66).
What is the impact of P-glycoprotein P-gp at the blood brain barrier?
Purpose: P-glycoprotein (Pgp) is an efflux transporter involved in transport of several compounds across the blood-brain barrier (BBB). Loss of Pgp function with increasing age may be involved in the development of age-related disorders, but this may differ between males and females.
What drugs inhibit P-glycoprotein?
Some common pharmacological inhibitors of P-glycoprotein include: amiodarone, clarithromycin, ciclosporin, colchicine, diltiazem, erythromycin, felodipine, ketoconazole, lansoprazole, omeprazole and other proton-pump inhibitors, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, verapamil.
What is PGP substrate?
What anticancer drugs would be affected by P-glycoprotein?
A plethora of anticancer drugs that are central to many chemotherapeutic regimes are susceptible to P-gp-mediated efflux (Figure 1), such as the microtubule-targeting vinca alkaloids (e.g. vinblastine and vincristine) and taxanes (paclitaxel and docetaxel), the DNA-chelating anthracyclines (doxorubicin and daunorubicin …
How is P-glycoprotein substrate specificity used in drug design?
Prediction of P-glycoprotein substrate specificity (S (PGP)) can be viewed as a constituent part of a compound’s “pharmaceutical profiling” in drug design.
Which is a non substrates in the PGP system?
Compounds with (N + O) > or = 8, MW > 400 and acid pKa > 4 are likely to be Pgp substrates, whereas compounds with (N + O) < or = 4, MW < 400 and base pKa < 8 are likely to be non-substrates. The obtained results support the view that Pgp functioning can be compared to a complex “mini-pharmacokinetic” system with fuzzy specificity.
What is the role of P-glycoprotein in drug absorption?
In vitro and in vivo studies have demonstrated that P-glycoprotein plays a significant role in drug absorption and disposition.
Are there species differences in P-glycoprotein transport?
On the other hand, there are significant species differences in P-glycoprotein transport activity between humans and animals, and the species differences appear to be substrate-dependent. Inhibition and induction of P-glycoprotein have been reported as the causes of drug-drug interactions.
