Excipients, considered “inactive ingredients,” are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. 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.
Pottel, Joshua; Armstrong, Duncan; Zou, Ling; Fekete, Alexander; Huang, Xi-Ping; Torosyan, Hayarpi; Bednarczyk, Dallas; Whitebread, Steven; Bhhatarai, Barun; Liang, Guiqing; Jin, Hong; Ghaemi, S. Nassir; Slocum, Samuel; Lukacs, Katalin V.; Irwin, John J.; Berg, Ellen L.; Giacomini, Kathleen M.; Roth, Bryan L.; Shoichet, Brian K.; Urban, Laszlo, The activities of drug inactive ingredients on biological targets, Science, Vol. 369, Issue 6502, pp. 403-413, DOI: 10.1126/science.aaz9906