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Host Pump Protein Can Affect Drug Actions

Similar but distinctive glycoproteins found along the membranes of several organs apparently serve as transport pumps for a wide variety of drugs and therefore can dramatically affect their activity in human hosts, according to Leslie Benet of the University of California, San Francisco. Thus, researchers developing new drug treatments--or evaluating familiar ones that do not work so effectively as they might--need to take into account the effects of these transport system on their products, he said during the symposium, ``Drug Transport Pumps: from Molecular Biology and Pharmacology to Clinical Implications,'' convened as part of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco, Calif., last September.

One of these multidrug resistance transporter P-glycoproteins (MRP1)--the first of several such systems that work in different ways and on different drugs--is found along cellular membranes in several human organs and tissues, including the adrenal glands, kidneys, the gastrointestinal (GI) tract, and probably as part of the blood-brain barrier, according to Benet. MRP1 serves as a very efficient efflux pump, acting on a wide array of drug molecules. For instance, it pumps drugs that enter cells along the villi (thin protuberances) of the GI tract back into the GI lumen. This location along villi of MRP1 is ``strategic,'' ensuring that ``any drug molecule in the intestine must go through this layer,'' he says.

MRP1's inherent actions, as well as its interactions with the cytochrome P450 detoxification system, can greatly affect a drug's activity. For example, this combined system can reduce the apparent efficacy of the immunosuppressive drug cyclosporin, which often is administered to organ transplant recipients to quell graft rejection, according to Benet. The same system also affects other immunosuppressive drugs as well the anticancer drug taxol.

Several years ago, wondering why cyclosporin shows ``poor bioavailability,'' Benet and his collaborators learned that the drug is subject to metabolism by the P450 system. By blocking that system with ketoconazole, which is better known as an antifungal drug, the bioavailability of cyclosporin shot up by 290%, he says.

However, the sharp change in bioavailability involves more than straightforward inhibition of this detoxification step, according to Benet. It also apparently depends on MRP1, which repeatedly pumps cyclosporin from GI cells into the lumen, providing the readily saturable P450 enzymes with additional opportunities to ``get rid of this xenobiotic.'' For several sets of drugs, he says, bioavailability depends not only on how much P450 enzyme is in the gut, but on ``how much access it has to drug because of the [actions] of the P-glycoprotein.''

MRP1 is not the only transporter system that acts on drugs, Benet says. For instance, some systems may facilitate drug absorption, whereas others may interfere with that process; still others seem to act exclusively on negatively charged compounds. Sometimes two or more systems may act simultaneously on a single drug, perhaps accounting for why bioavailability studies sometimes yield ``such varied results,'' he says ``There are now 9 or 10 transporters that we know so far, and we can expect more.''

Jeffrey L. Fox