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The activities of drug inactive ingredients on biological targets

Pottel, Joshua and Armstrong, Duncan and Zou, Ling and Fekete, Alexander and Huang, Xi-Ping and Torosyan, Hayarpi and Bednarczyk, Dallas and Whitebread, Steven and Bhhatarai, Barun and Liang, Guiqing and Jin, Hong and Ghaemi, Nassir and Slocum, Samual and Lukacs, Katalin and Irwin, John and Berg, Ellen and Giacomini, Kathleen and Roth, Brian and Shoichet, Brian and Urban, Laszlo (2020) The activities of drug inactive ingredients on biological targets. Science, 369 (6502). pp. 403-413. ISSN 1095-9203

Abstract

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 XXXXXX. 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 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.

Item Type: Article
Date Deposited: 15 Dec 2020 00:45
Last Modified: 15 Dec 2020 00:45
URI: https://oak.novartis.com/id/eprint/43103

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