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Michael Bartlett and Catherine White are trying to determine which anti-HIV/AIDS drugs or combination of drugs will provide the most protection for the fetus. They also are exploring the mechanisms by which the drugs are transported through the placenta. (Photo by Peter Frey)

Labor intensive
College of Pharmacy scientists are studying delivery of anti-HIV/AIDS drugs during pregnancy
By Sheila Roberson
roberson@rx.uga.edu
Catherine White and Michael Bartlett of UGA’s College of Pharmacy are looking at methods of drug delivery that will effectively control the spread of HIV/AIDS to infants during pregnancy.

Their findings could be of major significance to the large number of pregnant HIV-positive women in Sub-Saharan Africa who are in danger of spreading the disease to their babies.

Drug therapies for expectant women in the U.S. often include a four-drug combination given throughout pregnancy to decrease the viral load in the mother and inhibit transmission of the virus to the fetus. Additional drugs may be administered during labor and delivery.

Alternatively, in Third World countries, drug therapy is only begun at the onset of labor due to the expense and limited availability of the drugs. Since the viral load of the mother cannot be affected at that time, White and Bartlett are looking at which drugs or combination of drugs will provide the most protection for the fetus. If some drug compounds work better, medical personnel might be able to stretch the drugs to achieve the greatest effect.

Additionally, White and Bartlett are exploring the mechanisms by which the drugs are transported through the placenta. By conducting studies in animal models and cell cultures, they can look at passive and active transport methods. Rats are being used as test subjects because they have multiple fetuses and transporters similar to those in humans.

Studies have already shown that drugs cross the placenta by passive diffusion. Mothers have a higher concentration initially before diffusion occurs into the fetus. In active transport, influx transporters in the placenta move drugs into the fetal compartment and efflux transporters move drugs from the placenta back into the mother’s blood stream. 

In this study, pregnant rats are injected with the drugs normally used to treat HIV patients. The level of drug concentrations are measured over an eight-hour period in maternal plasma, the placenta, the fetus and amniotic fluid.

Since much research of this type has already been done on plasma levels, the UGA scientists are paying more attention to drug measurements in tissues.

Drugs are studied individually first and then in combination with other drugs. Some of the testing samples in rats are so small that they only have one chance to measure, says Bartlett, particularly for amniotic fluid, which might be only one drop.

If passive diffusion were the only method of drug transfer, then drugs given in combination should act the same as those given individually, according to Bartlett, who says they have found a significant difference when drugs are given together. 

Two different two-drug combinations have shown a 200 to 300 percent difference, either higher or lower, of exposure in the fetus. If too little drug reaches the fetus, then the fetus contracts the virus; too much will intoxicate the fetus.  

White says they expect that an active transport system is involved, with one drug blocking the other. White and Bartlett will continue to test different drug combinations and look more closely at which transporters might be involved. They know there are several transporters in the placenta but do not know which transporter family is responsible for transporting a particular drug or drug combination.

They hope to determine whether a drug has an affinity for a specific transporter and whether drugs compete for transporters through cell culture studies.

“If we see an effect in cell culture, then we will need to determine if it also happens in the animal model,” says Bartlett. “Our research is actually going in reverse from normal procedures. We are seeing effects in animals first and then looking at cell culture to determine the mechanism of action, rather than the other way around.”
 


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