Some 'inert' drug ingredients may be biologically active
Comprehensive laboratory study flags drug components in need of more
rigorous review

Date:
July 23, 2020
Source:
University of California - San Francisco
Summary:
Some supposedly inert ingredients in common drugs -- such as dyes
and preservatives -- may potentially be biologically active and
could lead to unanticipated side effects, according to a preliminary
new study.



FULL STORY ==========================================================================
Some supposedly inert ingredients in common drugs -- such as dyes and preservatives -- may potentially be biologically active and could lead
to unanticipated side effects, according to a preliminary new study by researchers from the UC San Francisco School of Pharmacy and the Novartis Institutes for BioMedical Research (NIBR).


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Most medications include only a relatively small amount of their active pharmaceutical ingredient by mass (for instance, the acetaminophen in
Tylenol and other medications). The rest of any given pill, liquid or injectable can be composed of ingredients including preservatives, dyes, antimicrobials and other compounds known as excipients. These ingredients
play critical roles in making sure a drug's active ingredient is delivered safely and effectively, as well as conferring important qualities like
shelf stability and the ability to quickly distinguish pills by color.

Excipients are generally accepted to be biologically inactive based on
their long history of use, or because they don't produce any obvious
toxicity in animal studies. But few studies have looked for more subtle
effects of long- term exposure to these compounds or how they might
interact in people who take multiple different medicines that include
these ingredients.

Researchers Brian Shoichet, PhD, of the UCSF Department of Pharmaceutical Chemistry and Laszlo Urban, PhD, Global Head of Preclinical Safety
Profiling at NIBR, had begun to wonder about whether all of these
substances were really inert, and joined forces to investigate them. They
began the work in 2017 with a database documenting most readily accessible
pure excipients, which the UCSF group had compiled in an easy-to-use
excipients browser, itself drawing on a more specialized FDA inactive ingredients database (IID), with support from the FDA-funded UCSF-Stanford Center of Excellence in Regulatory Science and Innovation (CERSI).

As reported in their new study, published July 23, 2020 online in Science,
the researchers have now systematically screened 3296 excipients contained
in the inactive ingredient database, and identified 38 excipient molecules
that interact with 134 important human enzymes and receptors.

The research team emphasizes that their study, which did not look for
actual effects on human patients, is only intended to flag molecules
with the potential to pose negative health effects, and the examples
they list will need to be further studied to understand how they might contribute to side effects of drugs in which they are found.



========================================================================== "These data illustrate that while many excipient molecules are in
fact inert, a good number may have previously unappreciated effects on
human proteins known to play an important role in health and disease,"
Shoichet said. "We demonstrate an approach by which drug makers could
in the future evaluate the excipients used in their formulations, and
replace biologically active compounds with equivalent molecules that are
truly inactive." The team used a couple of different approaches. At
UCSF, Shoichet's team computationally examined excipient molecules
that physically resemble the known biological binding partners of 3117 different human proteins in the public ChEMBL database. The team then computationally pared down 2 million possible interactions of these
excipients and human target proteins to 20,000 chemically plausible interactions. Based on visual inspection, the researchers identified
a subset of 69 excipients with highest likelihood of interacting with
human target proteins, and tested these interactions experimentally
in laboratory dishes, in collaboration with the groups of Bryan Roth,
PhD, a professor of pharmacology at the University of North Carolina,
Chapel Hill, and Kathy Giacomini, PhD, a professor of bioengineering at
UCSF and co-director of the UCSF-Stanford CERSI center.

These experiments identified 25 different biological interactions
involving 19 excipient molecules and 12 pharmacologically important
human proteins.

In a complementary set of experiments at NIBR, the researchers screened
73 commonly used excipients against a panel of human protein targets
involved in drug-induced toxicity and regularly used to test drug
candidates for safety.

They identified an additional 109 interactions between 32 excipients
and these human safety targets.

"Our study was meant to expand on anecdotal evidence that excipients
may be the culprits of unexpected physiological effects seen in certain
drug formulations," said study lead author Joshua Pottel, PhD, a former postdoctoral researcher in the Shoichet lab who is now President
and CEO of Montreal-based Molecular Forecaster Inc. "It was not so
surprising to find new properties of understudied compounds that have
been grandfathered in as 'inactive' for decades, but it was surprising
to see how potent some of these molecules are, especially considering
the fairly high quantities sometimes used in typical drug formulations."
The biologically active excipients the study identified in laboratory
dishes merit further study in animal models to establish whether any
of them may in fact produce unwanted side effects in human patients,
the authors said. Many should be readily interchangeable with truly
inert excipients of similar function, they said, but for others, new replacement compounds may need to be developed.

"After decades with little innovation in how drugs are formulated,
we see this as an opportunity for a public-private partnership between academic, regulatory, and pharmaceutical communities to seek new and
better excipients, and we demonstrate an approach to doing so," Shoichet
said. "Given the challenge this work presents to the pharmaceutical
status quo, we are grateful for the forward-thinking support the project
has received primarily from the FDA and through our collaboration with Novartis, in addition to the National Institutes of Health."

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Francisco. Original written by Nicholas
Weiler. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Joshua Pottel, Duncan Armstrong, Ling Zou, Alexander Fekete, Xi-Ping
Huang, Hayarpi Torosyan, Dallas Bednarczyk, Steven Whitebread,
Barun Bhhatarai, Guiqing Liang, Hong Jin, S. Nassir Ghaemi,
Samuel Slocum, Katalin V. Lukacs, John J. Irwin, Ellen L. Berg,
Kathleen M. Giacomini, Bryan L. Roth, Brian K. Shoichet, Laszlo
Urban. The activities of drug inactive ingredients on biological
targets. Science, 2020 DOI: 10.1126/ science.aaz9906 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200723172210.htm

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