SYNOPSIS
There is a physiological effect of thimerosal in humans that could alter dopamine receptor pathways which are associated with locomotion and more importantly, motor disorders.
TITLE
The activities of drug inactive ingredients on biological targets
CITATION
Joshua Pottel, et al.; The activities of drug inactive ingredients on biological targets;July 24, 2020; Science Vol. 369, No. 6502; DOI: 10.1126/science.aaz9906.
SUMMARY
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.
