Screening drug additives for biological activity

Inactive ingredients, or excipients, are ingredients added to medications that don't have a direct effect on the bodily function being treated. Rasi Bhadramani / iStock / Getty Images Plus

Both prescription and over-the-counter medicines list the active and inactive ingredients on the packaging. Active ingredients are those that have pharmacological activity, or a direct effect on the disease. Inactive ingredients, called excipients, are any other ingredients included in the medication. These can be fillers, flavorings, coatings, preservatives, and more.

Inactive ingredients are approved by the FDA and considered to be safe. They’re tested in animals for toxicity at the concentrations used in a medicine. Some have been used for decades in medicines based on these tests. However, technologies for studying the biological activity of drugs have greatly advanced over the years. In addition, some people may consume larger amounts of certain ingredients if they take multiple medications.

To further explore the possible biological activity of inactive ingredients, a research team led by Dr. Brian K. Shoichet at the University of California, San Francisco and Dr. Laszlo Urban at the Novartis Institutes for Biomedical Research took a two-part approach. Shoichet’s team computationally screened 639 excipients for potential activity against with more than 3,000 human targets, such different cell receptors. Urban’s team tested 73 excipients for their binding activity against targets chosen for their biological relevance, including 28 used for early drug safety evaluation.

The work was funded by NIH’s National Institute of General Medical Sciences (NIGMS) and National Institute of Mental Health (NIMH), along with the U.S. Food and Drug Administration. Results were published on July 24, 2020 in Science.

Using these two approaches, the researchers found 38 inactive ingredients with potential for biological activity. They tested 12 of these using cell-based assays. They chose those that are most frequently used in medicines and would cover a wide variety of purposes as drug additives. Seven compounds showed some biological activity, such as inflammation-related properties.

When medicines are taken orally, they’re first metabolized before getting into the bloodstream. So the researchers measured the concentration of the excipients that reached the bloodstream after being consumed in animals. Five out of the seven tested showed blood concentrations too low to be biologically active at their predicted targets. However, two compounds could reach high enough concentrations to potentially activate their predicted biological targets. Excipients that are injected directly into the body also showed biological activity.

“These data illustrate that while many excipient molecules are in fact inert, a good number may have previously unappreciated effects on human proteins known to play an important role in health and disease,” Shoichet says. “We demonstrate an approach by which drug makers could in the future evaluate the excipients used in their formulations, and replace biologically active compounds with equivalent molecules that are truly inactive.”

More studies are needed to determine whether the few potentially active excipients found in this study would have any unforeseen side effects in people—and, if so, in what amounts.

—by Tianna Hicklin, Ph.D.