'Virtual Stomach' Reveals Central Road That Helps Explain Drug Activation Variability

"We are predicting variables that we wish we could measure, but we cannot," says Dr. James G. Brasseur, professor of mechanical engineering, bioengineering and mathematics at Penn State. "Now that we know the Magenstrasse exists, we can look for it, but, it will not be easy to measure its existence and could require expensive technology."

Brasseur, working with Anupam Pal, research associate, Penn State and Bertil Abrahamsson, AstraZeneca, was interested in how the stomach empties its contents and how material passes from the stomach into the small intestines.

"The sphincter between the stomach and the small intestine is interactive," said Brasseur. "The sphincter opens and closes in a controlled way to regulate the flow of nutrient to the small intestines. Sensor cells in the intestines modulate the opening and closing."

Two types of muscle contractions control food movement in the stomach. One type of contraction, antral contractions, occur in the lower portion of the stomach and break down and mix stomach contents. The other type of contraction, fundic contractions, is over the upper surface of the stomach. It was thought that the fundic contractions move food from the top of the stomach where it enters from the esophagus, to the bottom of the stomach where the chyme leaves and enters the small intestine. The assumption was that particles left the stomach in the same order they entered the stomach.

The researchers modeled the stomach contents and discovered that a narrow path forms in the center of the stomach along which food exits the stomach more rapidly than the regions near the walls of the stomach. They used MRI data from human subjects to create the proper geometry of the muscle contractions.

"We looked at a ten-minute window of digestion and we tagged all the particles as they left the virtual stomach," said Brasseur. "We then reversed the flow on the computer and saw where the particles came from."

In essence they ran the simulation backwards and were surprised to see a central road appear. Those particles in the virtual stomach that were on the central road, exited the stomach in 10 minutes. The Magenstrasse extended all the way from the stomach's exit up to the top of the stomach's fundus. Material that entered the stomach off this Magenstrasse could remain in the stomach a long time, even hours in the real stomach.

"This discovery might explain observed high variability in drug initiation time, and may have important implications to both drug delivery and digestion," the researchers report online in the Journal of Biomechanics. The paper will appear in a print edition in 2007.

Because most drugs target the small intestines for absorption, a pill disintegrates in the stomach and activates in the small intestines. With this new understanding of how the stomach works, where in the stomach a pill or capsule disintegrates becomes very important. Drug delivery times may differ from 10 minutes to hours depending on location.

"Therefore, drugs released on the Magenstrasse will enter the duodenum rapidly and at a high concentration," the researchers report. "Drug released off the gastric emptying Magenstrasse, however, will mix well and enter the duodenum much later, at low concentration."

For some drugs, rapid release is important, for others, slow release over long periods of time is the desired outcome.

"If you do not know a Magenstrasse exists, you will not factor it into the designs," says Brasseur. "Now that we know, perhaps researchers can design pills with higher densities to sit around at the bottom of the stomach, outside the Magenstrasse, and let the drug out slowly."