Some “inactive” drug ingredients may be biologically active

Preliminary new research by researchers at the University of California San Francisco and Novartis Institute of BioMedical Research shows that some inactive ingredients in common drugs such as dyes and preservatives are biologically active and unexpected May cause side effects (NIBR).

Most drugs contain only relatively small amounts of active pharmaceutical ingredients (eg, Tylenol acetaminophen and other drugs). The remaining pills, liquids or injections can consist of ingredients including preservatives, dyes, antibacterial agents, and other compounds known as excipients. These ingredients play an important role in ensuring that the active ingredients of the drug are delivered safely and effectively and also have important qualities such as storage stability and the ability to quickly distinguish tablets by color. Grant

Excipients are generally accepted to be biologically inactive based on their long history of use or because they do not produce overt toxicity in animal studies. However, few studies have explored the more subtle effects of long-term exposure to these compounds, or how they interact in people taking multiple different drugs containing these ingredients.

Dr. Brian Shoichet of the UCSF Pharmaceutical Chemistry Department and Dr. Laszlo Urban, Global Head of Preclinical Safety Profiling at NIBR, began to question whether all of these substances were truly inert and the power to investigate them. They started in 2017 with a database that documents the most easy-to-use pure excipients. UCSF Group is a FDA-funded UCSF Stanford Center of Excellence of Regulars, edited with an easy-to-use Excipient Browser and utilizing FDA’s Inert Ingredients Database (IID), which is itself more specialized. Tree Science and Innovation (CERSI).

July 23, 2020, as reported in their new study, ScienceResearchers have now systematically screened 3296 excipients in the inactive ingredient database and identified 38 excipient molecules that interact with 134 key human enzymes and receptors.

The research team, which did not look for actual effects on human patients, intended their research to only flag molecules that could have adverse health effects, and the examples they list are: It emphasizes that further research needs to be done to understand how they can contribute to the side effects of the drugs they were discovered.

“These data, while many excipient molecules are actually inactive, could have previously unrecognized effects on human proteins known to play important roles in health and disease. It shows that there is sex,” Shoichet said. “We show an approach in the future that allows pharmaceutical companies to evaluate the excipients used in their formulations and replace biologically active compounds with truly inert equivalent molecules.”

The team used several different approaches. At UCSF, Shoichet’s team computationally investigated excipient molecules physically similar to known biological binding partners of 3117 different human proteins in the public ChEMBL database. The team then reduced the 2 million possible interactions of these excipients with human target proteins to 20,000 computationally plausible interactions. Based on visual inspection, researchers identified a subset of the 69 excipients most likely to interact with human target proteins and collaborated with a group of pharmacology professors Bryan Roth, Ph.D. Dr. Kathy Giacomini, a professor of biology at UCSF and co-director of UCSF Stanford CERSI Center, has ly tested these interactions in a laboratory dish at the University of North Carolina at Chapel Hill.

These experiments identified 25 different biological interactions involving 19 excipient molecules and 12 pharmacologically important human proteins.

In a complementary series of experiments at NIBR, researchers found that 73 commonly used targets for a series of human protein targets involved in drug-induced toxicity and regularly used for safety testing of drug candidates. Excipients were screened. They found that there were an additional 109 interactions between 32 excipients and these human safety goals.

“Our study was intended to expand further on anecdotal evidence that excipients may be responsible for the unexpected physiological effects seen in certain formulations,” lead author Joshua.・Dr. Potter said. President and CEO of Montreal-based Molecular Forecaster Inc. “It was not so surprising to find new properties for under-studied compounds that have been described as “inactive” for decades. In particular, consider the fairly large amounts sometimes used in typical drug formulations. “

According to the authors, the biologically active additives identified in the study in the laboratory tableware will be further studied in animal models to see if they actually cause unwanted side effects in human patients. Worthy of. Many have to be easily interchangeable with truly inert excipients of similar function, they said, but for others it may be necessary to develop new alternative compounds. ..

“Over the decades, there has been little innovation in the way pharmaceuticals are formulated, and we see this as an opportunity for public-private partnerships between the academic, regulatory and pharmaceutical industries to explore new and better excipients, It shows an approach for that,” Shoichet said. “Given the challenges this research poses to the current state of the pharmaceutical industry, the project is grateful for the forward-thinking support received primarily from the FDA and through collaboration with Novartis in addition to the National Institutes of Health.”