P-glycoprotein is an ATP-dependent transporter which is capable of transporting an extremely wide variety of drugs out of the cell. The potential role for P-glycoprotein for determining the oral bioavailability of some drugs has only recently been appreciated66. P-glycoprotein is expressed in a variety of normal human tissues including the liver, brain, adrenal gland, kidney and intestinal tract epithelia67. This suggests a common role as a protective mechanism. In the small intestine it is localised in the apical membranes of the cell, but is not detectable in crypt cells. It is composed of two blocks each containing six trans-membrane regions and a site for binding ATP on each half (Figure 6.12).
The mechanism by which such a wide range of compounds is transported is unknown, but it appears that the drug is effluxed by flipping the drug from the inner to the outer leaflet of the bilayer membrane68. This model is consistent with the ability of compounds to penetrate lipid and the common denominator is that the P-glycoprotein substrates are hydrophobic and amphipathic in nature. The number of drugs that can be effluxed from the cell by P-glycoprotein include the immunosuppressive agent cyclosporin A, vinca alkaloids, digoxin, E-blockers69, erythromycin, antibiotics and cimetidine. The molecular weight of the compounds transported varies enormously and encompasses a range between 250 to 1850 Daltons (Gramicidin D). P-glycoproteins were originally identified by their ability to transport cytotoxic drugs out of certain types of tumour cells thus conferring resistance. This mechanism appeared to work against a range of drugs and gave rise to the concept of "multi-drug resistance" (MDR).
The therapeutic potential of inactivating this receptor protein has led to the search for non-cytotoxic drugs with the ability to block transport and increase influx to the target cells.
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