Peter Swaan, PhD, a professor in PSC, and director of the Center for Nanomedicine and Cellular Delivery, has devoted his career to studying issues related to drug absorption. Why, for instance, are so many drugs poorly absorbed, and what can be done to correct that?
When he greeted his healthy baby son, Adriaan, into the world five years ago, he started thinking about an unexplored aspect of drug absorption. Many women take drugs during pregnancy to treat conditions such as preeclampsia, hypertension, and depression. Yet little is known about how readily these drugs cross the placenta to the fetus, where they could potentially do harm.
“No one thinks about drug absorption in pregnancy and babies,” says Swaan, noting that the problem mercifully wasn’t an issue in his son’s birth.
His curiosity drove him to study the mechanisms of placental transport, and to design a clinical trial to study the absorption of anti-hypertensive drugs given to women with preeclampsia and early contractions.
Pending grant approval, School of Pharmacy researchers collaborating with colleagues at the University of Kansas Medical Center will analyze blood samples from the umbilical cords of hundreds of babies born to women taking anti-hypertensives. Their goal is to relate different rates of absorption with genetic variability in order to develop personalized treatment plans for each individual.
Swaan envisions the School of Pharmacy as part of a multicenter consortium in which researchers from other world-class institutions will study the fetal absorption of antibiotics used in the prevention of group B strep infections, a leading cause of infant mortality.
Swaan, a native of the Netherlands who earned his pharmacy and doctoral degrees at Utrecht University and came to the School of Pharmacy in 2002, has focused primarily on oral drug delivery. Tablets and capsules taken by mouth are absorbed through the gastrointestinal tract, but at different rates depending on the medication and the person’s genetic makeup. Poorly absorbed drugs include oral insulin, acyclovir, cancer agents, and antiretrovirals for HIV.
“A lot of drugs are highly efficacious, but they get poorly absorbed so you have to give them at very high doses and the side effects can be high,” says Swaan. Absorption rates may vary from 5 to 20 percent for a particular drug, leaving quite a bit of uncertainty when it comes to prescribing an appropriate dose.
To solve this, Swaan considered how he might enable drugs to pass more readily through the intestinal wall. He turned to bile acid transporters, proteins that sit on the wall of the gut and reabsorb bile that goes unused in the digestion of fats. Transporters are gateways for the passage of bile salts across the intestinal wall, so they are potential targets to facilitate the movement of drug molecules that under normal circumstances are absorbed poorly.
Swaan’s hypothesis involves chemically attaching drug molecules onto synthesized bile salts, which then secrete the drugs across. “By coupling drugs to bile acids we can significantly increase their oral bioavailability,” he says. This calls for rational design: defining the chemical dimensions tolerated by the transporter so the piggybacked drug can move across.
However, the first step is to solve the structural features of the protein responsible for intestinal absorption. “Since this protein is membrane-embedded, and thus difficult to work with,” he says, “we employ a multi-pronged approach involving molecular biology, biophysics, and computational techniques.”
This article was written by Jonathan Bor for the Summer 2009 edition of Capsule.
