Continuing to beat the drum on this potentially harmful fact: Both prescription (Rx) and over-the-counter (OTC) medications frequently contain the same unwanted additives (including preservatives, antimicrobials, dyes) that consumers are intentionally avoiding in their food. These additives are commonly listed as “inactive” on the drug label–not because these ingredients are necessarily inactive in the body, but because they are not a part of those ingredients that have a direct effect on whatever symptom the drug is manufactured to treat.
Also known as “excipients”, these so-called “inactive” or “inert” additives are found in pill form, liquids and injectable medications. Sometimes these additives are included to help preserve the medication, sometimes to extend the drug’s shelf life, sometimes to maintain consistency in texture, sometimes as fillers or binders of the active ingredients, and other times to give the drug a dose-specific color (such as a 5 mg pill is orange, while the 10 mg version is blue).
The problem, as we have sounded the alarm about for many years, is that while these additives may not have a direct effect on whatever the person’s symptoms are, they hold the potential for triggering health-related problems of their own*. And unfortunately, few studies have examined what happens when consumers have allergic or toxic reactions to these additives, or the potential effects of long-term exposure to these compounds, or how they might interact in people who take multiple different medicines that include these additives.
*Examples include Tartrazine/Yellow Dye 5 in asthma medicines, Red Dye 40 in children’s cough medicines, and Blue Dye 1 and Blue Dye 2 in drugs for gastrostomy tubing.
With support from the U.S. National Institutes of Health (NIH) and FDA-funded UCSF-Stanford Center of Excellence in Regulatory Science and Innovation (CERSI), about three years ago scientists began to investigate whether all of these substances (aka “inactive” ingredients/additives in medications) were really inert. They began with a database documenting most readily accessible pure excipients, which have been compiled in an easy-to-use excipients browser (itself drawing on a more specialized FDA inactive ingredients database (IID)).
Researchers systematically screened 3,296 excipients contained in the “inactive ingredient” database, and identified 38 excipient molecules that interact with 134 important human enzymes and receptors.
One of the research teams computationally examined excipient molecules that physically resemble the known biological binding partners of 3,117 different human proteins in the public ChEMBL database. The team then computationally pared down 2 million possible interactions of these excipients and human target proteins to 20,000 chemically plausible interactions. Based on visual inspection, the researchers identified a subset of 69 excipients with highest likelihood of interacting with human target proteins, and tested these interactions experimentally in laboratory dishes.
In a complementary set of experiments at NIBR, the researchers screened 73 commonly used excipients against a panel of human protein targets involved in drug-induced toxicity and regularly used to test drug candidates for safety. They identified an additional 109 interactions between 32 excipients and these human safety targets.
All in all, these experiments identified 25 different biological interactions involving 19 excipient molecules and 12 pharmacologically important human proteins.
“It was not so surprising to find new properties of understudied compounds that have been grandfathered in as ‘inactive’ for decades, but it was surprising to see how potent some of these molecules are, especially considering the fairly high quantities sometimes used in typical drug formulations.”
-Joshua Pottel, PhD, President and CEO, Molecular Forecaster Inc.
“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.
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.”
-Brian Shoichet, Ph.D., Department of Pharmaceutical Chemistry, University of California, San Francisco
Journal Reference: Pottel, J., et al., The activities of drug inactive ingredients on biological targets, Science 24 Jul 2020: Vol. 369, Issue 6502, pp. 403-413.