The activities of drug inactive ingredients on biological targets

Excipients are a major component of formulated drugs and play key roles in their pharmacokinetics. Excipients need to be stable in nature and have no contraindications for the main drug. It is harmless to the human body, has no physiological effect, does not affect the curative effect, and does not give the main drug to produce chemical or physical effects. Therefore, excipients are considered “inactive ingredients” in the drug. However, a recent study published in the "Science" magazine shows that some excipients are not as inactive as imagined, and may have activity against medically relevant molecular targets.

Researchers from the Novartis Institute of Biomedical Research and the University of California, through large-scale computational screening and targeted experimental tests, found that 38 approved excipients have 134 previously unknown activities: in vitro tests revealed 25 excipients Agent activity, ranging from low nanomolar to high micromolar. By testing against clinically safe targets, the researchers determined the activity of another 109 excipients. This proves that the "inactive" components that are ubiquitous in many drugs have direct activity on biologically relevant molecules in vitro.

In cellular models, the five excipients have a predictable system-level toxicity signature. In the study, some people were exposed to 7 excipients. Although most of them are suspected of not reaching dangerous exposure concentrations, the results suggest that two excipients (ie thimerosal and cetylpyridine) will It reaches a concentration that overlaps with their binding activity to dopamine receptor D3 in vitro.

These findings indicate that although most excipients should be inert and unable to enter the body’s circulation, many approved excipients may directly modulate physiologically relevant targets and may affect enzymes, receptors, and others in unexpected or even harmful ways，the function of protein.

References: Joshua Pottel, Duncan Armstrong, Ling Zou, Alexander Fekete, Xi-Ping Huang, Hayarpi Torosyan,et al.The activities of drug inactive ingredients on biological targets.[J]Science,DOI: 10.1126/science.aaz9906