P-gp (ABCB1) Introduction

What are P-glycoproteins?

P-gp (ABCB1) appears to have developed as a mechanism to protect the body from harmful substances. Using ATP as an energy source, they transport certain hydrophobic substances in the following directions:

They play a large role in the distribution and elimination of many clinically important therapeutic substances. Prescription and OTC drugs, foods and substances made by the body may be inhibitors and/or inducers of these transporters. Some drugs like cyclosporine are both substrates and inhibitors of P-gp (ABCB1), other drugs like nifedipine are inhibitors only and some drugs like digoxin are only substrates.

Since P-gps block absorption in the gut, they should be considered part of the "first-pass effect". In fact, they can "set up" or act as "gatekeepers" for later P450 cytochrome actions. If one drug is a substrate of both P-gp and CYP3A4 (both found in close proximity in the intestinal wall), and a second drug is added that is an inhibitor of both P-gp and CYP 3A4 (e.g., ketoconazole, erythromycin, mibefradil), then the first drug will be allowed in increased amounts. Since CYP3A4 is inhibited, levels of unmetabolized drug will enter the blood. The effect of P-gp blockade is to "open the gates" so that the later actions of CYP3A4 inhibition will be increased.

Another example is loperamide and quinidine. Loperamide is an opiate antidiarrheal that is normally kept out of the brain by the blood brain barrier due to transport away from the brain by P-gp. When given with quinidine which inhibits P-gp, more loperamide can enter the brain and cause respiratory depression (Sadeque 2000).

Since ABCB1(P-gp) kinetics are "saturable", ABCB1s(P-gps) can play a part in drug interactions only when the therapeutic concentration of the substrate drug is low [e.g., digoxin, fexofenadine, talinolol,). Many factors can alter ABCB1(P-gp) function and influence ABCB1(P-gp)-based interactions. Genetic differences of ABCB1(P-gp) are known to exist, and more than 100 variations have been identified, most of them, single nucleotide polymorphisms (SNPs). A polymorphism at exon 26 (C3435) has been shown to influence the level of intestinal ABCB1(P-gp) and the concentration of digoxin: C3435TT with decreased ABCB1(P-gp) and increased digoxin. This genotype has also been shown to be a risk factor for the side effect of orthostatic hypotension of the ABCB1(P-gp) substrate nortriptyline . There are racial differences of this polymorphism. Women may have significantly lower hepatic ABCB1(P-gp) levels than men, which may account for more efficient metabolism of certain drugs by women.

P-gp (ABCB1) has been implicated as a primary cause of multidrug-resistance in tumors. The responsible gene- has been found to be MDR1. Many oncological drugs are ABCB1(P-gp) substrates and are excluded from the brain at the blood-brain barrier (BBB). In cases of primary or secondary brain tumors, if an ABCB1(P-gp) inhibitor could be found that would block the extrusion of the oncological drug from the BBB without causing toxicity, the efficacy of such drugs might be improved. Several generations of ABCB (P-gp) inhibitors have been evaluated with modest success. A recent study of paclitaxel with elacridar [a third generation ABCB1(P-gp) inhibitor] has shown promise. A similar targeted strategy for improving drug efficacy could be useful for a wide range of brain disorders, from HIV and other infections to mood disorders.

An understanding of the physiological regulation of these transporters is key to designing strategies for the improvement of therapeutic efficacy of drugs that are their substrates for P-gp activity (Sukhai 2000). A list of P-gp (ABCB1) substrates, inhibitors and inducers is available here .

References