Protease inhibitors are a powerful tool to fight HIV, but they have two big problems: They are rapidly cleared from the bloodstream, and they are blocked to enter the brain, where HIV can be devastating. Now a report this month of Journal of Clinical Investigation suggests a possible way around these problems. This strategy could make the most effective protease inhibitors and to lower the cost of treatment.
The patients taking protease inhibitors can have dramatic reductions in HIV rates. But the amount of drug that gets into the blood stream can vary widely, and doctors are struggling to maintain the levels of a stable patient medications. "You can give the same dose to 10 people, and the blood levels can be very variable," said Richard Kim, a clinical pharmacologist at the Medical School of Vanderbilt University. Kim thought that the molecular pumps called p-glycoprotein can be kept low blood levels. These molecules help block toxins from entering the bloodstream by lining cells of the small intestine, and they help the liver and kidneys to eliminate toxins through the bile and urine. They also play a key role in maintaining the blood brain barrier preventing toxins from entering the brain.
To test whether p-glycoprotein hampers treatment against AIDS, Kim scored three inhibitor drugs protease town with a radioactive marker. It was then fed normal drugs in mice and of mice bred to lack of p-glycoproteins. After 4 hours, he checked the organs of animals for radioactivity. In normal mice, radioactive drugs were concentrated in the intestine, and those done through the defenses of the intestine were collected in the kidney and liver. Brain concentrations of the protease inhibitor were only 10% of those of any other tissue
In mice that lack p-glycoproteins, drugs were two to five times more concentrated in blood plasma -. And from 10 to 40 times more concentrated in the brain - that in mice at the molecular pump. Kim concludes that the absence of p-glycoproteins allowed more than one medicament through the intestine and the blood brain barrier, and less has been removed by the kidneys or liver. It suggests that doctors blocking p-glycoproteins can get better results with lower doses, reducing processing costs. p-glycoprotein inhibitors are currently used to help drug against cancer in and kill tumor cells.
Michael Gottesman, a cell biologist at the National Cancer Institute, says the p-glycoprotein blocking looks like a promising way to improve the treatment of protease inhibitor, but cautions that these molecules could do drugs against AIDS more toxic. In mice that lack of p-glycoproteins, he said, a drug product standard narcotic side effects antidiarrheal. He suspects similar problems may occur in patients with AIDS "You could see some funny side effects of drugs from entering the brain," he said.
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