PGP Introduction

This Web page tracks current data on P-glycoproteins (PGPs). Jessica R Oesterheld, M.D. is the primary person scouring the literature. She welcomes help since this is a burgeoning area of research. We physicians are just now realizing the significance of PGP-mediated drug interactions.

What are P-glycoproteins? P-glycoproteins are part of a larger family of efflux transporters found in the gut, gonads, kidneys, biliary system, brain and other organs. They appear 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:

PGPs 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 cyclosporin are both substrates and inhibitors of PGP, other drugs like nifedipine are inhibitors only and some drugs like digoxin are only substrates.

Since PGPs 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 PGP and CYP3A4 (both found in close proximity in the intestinal wall), and a second drug is added that is an inhibitor of both PGP 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 PGP blockade is to "open the gates" so that the later actions of CYP3A4 inhibition will be increased.

P-Glycoprotein, is a 170 kDa membrane-bound protein which has been implicated as a primary cause of multidrug-resistance in tumors. An understanding of the physiological regulation of these transporters is key to designing strategies for the improvement of therapeutic efficacy of drugs which are their substrates. "PGP activity is controlled by a variety of endogenous and environmental stimuli which evoke stress responses including cytotoxic agents, heat shock, irradiation, genotoxic stress, inflammation, inflammatory mediators, cytokines and growth factors" (Sukhai 2000).

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 PGP. When given with quinidine which inhibits PGP, more loperamide can enter the brain and cause respiratory depression (Sadeque 2000).

P-Glycoprotein, is a 170 kDa membrane-bound protein which has been implicated as a primary cause of multidrug-resistance in tumors. The responsible gene- MDR1 has recently been reclassified as part of the ABCB subfamily and rename PGY-1, and a website of ATP-Binding Cassette Transporters has been established at http://nutrigene.4t.com/humanabc.htm. 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 PGP activity (Sukhai 2000).

References

Hedman A, Meijer DK. The stereoisomers quinine and quinidine exhibit a marked stereoselectivity in the inhibition of hepatobiliary transport of cardiac glycosides.
J Hepatol. 1998 Feb;28(2):240-9.
Koren G, Woodland C, Ito S. Toxic digoxin-drug interactions: the major role of renal P- glycoprotein.Vet Hum Toxicol. 1998 Feb;40(1):45-6.
Sadeque AJ, Wandel C, He H, Shah S, Wood AJ. Increased drug delivery to the brain by P-glycoprotein inhibition.Clin Pharmacol Ther. 2000 Sep;68(3):231-7.
Sukhai M, Piquette-Miller M.Regulation of the multidrug resistance genes by stress signals.J Pharm Pharm Sci. 2000 May-Aug;3(2):268-80

5/1/02