The University Record, September 8, 1992

Pharmacy researchers discover biological ‘Trojan Horse’

By Sally Pobojewski
News and Information Services

College of Pharmacy researchers have developed a biochemical “Trojan horse” designed to smuggle oral medication through gastrointestinal tract membranes and into the bloodstream before the drug is destroyed during the digestive process.

In recent tests of the technique using alpha-methyldopa (marketed as Aldo-met)—a common generic drug used to treat high blood pressure— scientists increased absorption of the drug’s active ingredient from 33 percent to nearly 90 percent in laboratory rats, according to Gordon L. Amidon, professor of pharmaceutics.

Amidon presented details of the research during the American Chemical Society Meeting in Washington, D.C., in late August.

Amidon said the U-M research program focuses on development of prodrugs—a class of drugs whose pharmacological action is released when the drug is metabolized within the body. Several research laboratories worldwide are investigating prodrugs, but Amidon maintains the U-M approach has produced the highest increases in drug delivery levels reported to date.

To be effective, Amidon said prodrugs designed for oral administration must be based on an in-depth knowledge of how the digestive system works. He explained that absorption of some oral medication is compromised by a chemical process called protein hydrolysis taking place within the gastrointestinal tract that rapidly breaks down food and drug compounds into elementary proteins, amino acids and other nutrients.

Some medications, particularly those with a large and complex molecular structure, are particularly vulnerable to this process, Amidon explained. As examples, he cited an antihypertensive drug called lisinopril (marketed as Prinivil), a diuretic called furosemide (Lasix), and a drug used to treat osteoporosis called calcitonin (Calcimar).

“Only 20 percent of the active ingredient in lisinopril, just 40 percent of furosemide, and less than 1 percent of calcitonin ever makes it to the patient’s bloodstream where it can do some good,” Amidon said. “Pharmaceutical firms strive for at least a 60 percent bioavailability in new drug compounds, but accept 10 to 20 percent when there are no alternatives. Our approach offers some new strategies for increasing the bioavailability to at least 60 percent.”

U-M researchers use simple proteins called peptides as the base material in their prodrug production process. Using a series of biochemical procedures, scientists remove one amino acid cluster from the peptide molecule and replace it with a specific prodrug compound designed to resist the destructive metabolic processes within the GI tract.

Once in the intestine, peptide molecules—carrying the prodrug “hidden” within them—pass easily into cells lining the wall of the intestine. Once inside these cells, the peptide prodrug reacts chemically with enzymes present in the cell fluid to produce the drug’s active ingredient, which then diffuses through the outer intestinal cell wall into blood vessels on the other side.

Amidon said the U-M prodrug techniques have the potential to improve the effectiveness of many hard-to-absorb oral medications currently used to treat cardiovascular diseases, osteoporosis and other illnesses. Improving absorption also may help reduce side effects from these medications, Amidon explained, by limiting the amount of unabsorbed drug compounds that remain in the digestive system.

“These results are just one example of the potential benefits from drug delivery research,” Amidon said. “Pharmaceutical firms tend to concentrate on new drug design. Little capital or creativity has been invested in drug delivery. Without sophisticated drug delivery techniques, though, it’s like designing a high-tech engine and putting it in a Model-T chassis.”

Graduate student Mandana Asgharnejad is a co-researcher on the alpha-methyldopa experiment. Henry I. Mosberg, associate professor of medicinal chemistry, is a co-investigator on the prodrug research program, which is funded by the National Institutes of Health.