Inert Ingredients in Drugs Actually Might Have More Effects Than Realized

San Francisco—Inert ingredients in common drugs—including dyes and preservatives—are usually considered to be beside the point when evaluating a prescription product. But what if those ingredients actually are potentially biologically active and could lead to unanticipated side effects, a preliminary study asks.

Researchers from UC San Francisco School of Pharmacy and the Novartis Institutes for BioMedical Research point out that most medications include only a relatively small amount of their active pharmaceutical ingredient by mass. Making up the rest of any pill, liquid or injectable are preservatives, dyes, antimicrobials, and other compounds known as excipients.

The article in the journal Science explains that the additional ingredients make sure a drug’s active ingredient is delivered safely and effectively, while also adding benefits such as shelf stability and the ability to quickly distinguish pills by color.

“Most drug formulations comprise mainly inactive ingredients known as excipients. Excipients are tested in animal studies and do not display toxicity at allowed concentrations, but their interaction with molecular targets has not been systematically explored,” the researchers write, citing past studies that examined excipient activity by combining large-scale computational screening with targeted experimental testing.

The authors note that 38 excipients with activities against 44 targets were identified, adding, “Several excipients were active in cell panels that predict tissue-level toxicity, and two are suggested to reach concentrations in vivo that overlap with their in vitro activities. Although most excipients are inert, some have activity that deserves further consideration.”

The study team computed the likelihood that approved excipients would bind to molecular targets, and used in vitro testing to reveal 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. The group pinpointed another 109 activities by testing against clinical safety targets.

“In cellular models, five excipients had fingerprints predictive of system-level toxicity,” according to the study. “Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant Kd values of 320 and 210 nM, respectively. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets.”


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