Pumping Up AIDS Drugs

Protease inhibitors are a powerful tool for battling HIV, but they have two big problems: They are quickly removed from the bloodstream, and they are blocked from entering the brain, where HIV can have devastating effects. Now, a report in this month's Journal of Clinical Investigation suggests a possible way around both problems. This strategy could make protease inhibitors more effective and bring down the cost of the treatment.

Patients taking protease inhibitors can have dramatic reductions in HIV levels. But the amount of drug that gets into the bloodstream can vary dramatically, and doctors struggle to keep a patient's drug levels steady. "You can give the same dose to 10 people, and blood levels can be quite variable," says Richard Kim, a clinical pharmacologist at Vanderbilt University Medical School. Kim thought that molecular pumps called p-glycoproteins might be keeping blood levels down. These molecules help to block toxins from entering the bloodstream by lining intestine cells, and they aid the liver and kidney in eliminating toxins through bile and urine. They also play a key role in maintaining the blood-brain barrier by preventing toxins from entering the brain.

To test whether p-glycoprotein hinders AIDS treatments, Kim labeled three common protease inhibitor drugs with a radioactive tag. He then fed the drugs to normal mice and to mice bred to lack p-glycoproteins. After 4 hours, he checked the animals' organs for radioactivity. In normal mice, the radioactive drugs were concentrated in the intestine, and those that made it through the intestine's defenses were pooled in the kidney and liver. The brain concentrations of protease inhibitor were just 10% of those in any other tissue.

In mice that lack p-glycoproteins, the drugs were two to five times more concentrated in blood plasma--and 10 to 40 times more concentrated in the brain--than in mice with the molecular pump. Kim concludes that the lack of p-glycoproteins allowed more of a drug to pass through the intestine and blood-brain barrier, and less was eliminated through the kidney or liver. He suggests that by blocking p-glycoproteins doctors can get better results with lower doses, cutting treatment costs. Inhibitors of p-glycoproteins are currently used to help cancer drugs enter and kill tumor cells.

Michael Gottesman, a cellular biologist at the National Cancer Institute, says that blocking p-glycoproteins looks like a promising way to improve protease inhibitor treatments, but he warns that these molecules could make some AIDS drugs more toxic. In mice that lack p-glycoproteins, he says, a standard antidiarrhea drug produces narcotic side effects. He suspects similar problems may occur in AIDS patients "You might see some funny side effects from drugs getting into the brain," he says.

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