The activities of drug inactive ingredients on biological targets

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 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.

A human stem cell-derived test system for agents modifying neuronal N-methyl-d-aspartate-type glutamate receptor Ca2+-signalling

“…There is a range of possibilities to establish test methods for glutamate receptor interactions. Typical pharmacological binding assays, as used for advanced drug candidates are at one end of the spectrum (Berger et al 2012 ; Pottel et al 2020 ). The disadvantages of these assays are the uncoupling from the natural physiological environment, and that adversity is hard to define.…”

Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response

“…CrEL is the first excipient that renders paclitaxel sufficient solubility to achieve therapeutical benefit in patients. The present study uncovers the complex role of CrEL on metabolism and inflammation in cultured human cancer and primary immune cells and highlights the need to thoroughly investigate the biological effects of excipients, an overlooked gap between basic and clinical research ( Pottel et al., 2020 ). Further investigations using animal models, such as various conditional ANGPTL4 knockout mice ( Aryal et al., 2019 ), are needed to clarify the in vivo relevance of these molecular mechanisms.…”

Use of an antiviral mouthwash as a barrier measure in the SARS-CoV-2 transmission in adults with asymptomatic to mild COVID-19: a multicentre, randomized, double-blind controlled trial

“…Second, their salivary viral load significantly decreased over the T1-T3 period in both groups; however, there was a more positive impact in the CDCM group than in the placebo group. The decrease observed in the placebo group could be explained by the natural decrease in salivary viral load over the course of a day, by the effect of oral rinsing or by the presence of excipients that can be considered as potential active ingredients [ 23 ]. Third, for patients with initial loads greater than 4.01 log 10 copies/mL, a higher but nonsignificant percentage of viral load reduction was observed for the CDCM group than for the placebo group.…”