Remdesivir potently inhibits carboxylesterase-2 through covalent modifications: signifying strong drug-drug interactions
Shen et al.
, Remdesivir potently inhibits carboxylesterase-2 through covalent modifications: signifying strong drug-drug..
, Fundamentals of Clinical Pharmacology, doi:10.1111/fcp.12643
Analysis finding that remdesivir at nanomolar concentrations inhibits carboxylesterase-2 (CES2) through covalent modifications. CES2 is a major drug metabolizing enzyme. Authors conclude that caution must be exercised when remdesivir is used along with drugs hydrolyzed by CES2.
Shen et al., 28 Dec 2020, peer-reviewed, 3 authors.
Abstract: doi: 10.1111/fcp.12643
Remdesivir potently inhibits
carboxylesterase-2 through covalent
modifications: signifying strong drug-drug
Yue Shen, William Eades, Bingfang Yan
Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH,
Received 15 November 2020;
revised 23 December 2020;
accepted 23 December 2020
Remdesivir was recently approved to treat COVID-19. While this antiviral agent
delivers clinical benefits, several safety concerns in many cases have been raised.
This study reports that remdesivir at nanomolar concentrations inhibits carboxylesterase-2 (CES2) through covalent modifications. CES2 is a major drug-metabolizing enzyme. The combination of high potency with irreversible inhibition
concludes that cautions must be exercised when remdesivir is used along with
drugs hydrolyzed by CES2.
Bingfang Yan, Division of
Pharmaceutical Sciences, James
L. Winkle College of Pharmacy,
University of Cincinnati,
Cincinnati, OH 45229, USA.
This work was supported by
National Institutes of Health
Grants R01 EB018748 and
R21AI153031-01 (Yan B).
The pandemic of coronavirus disease 2019 (COVID-19)
has become a health crisis with the global death toll
passing one million. So far, there are limited options to
treat COVID-19. Remdesivir was granted emergency
use authorization based on promising clinical benefits.1-3 Even with remdesivir, the rate of serious adverse
events and mortality was high.1-3 The precise mechanisms remain unclear. Nevertheless, COVID-19 patients
frequently receive multiple drugs and remdesivir
requires metabolism for its therapeutic activity1-3;
therefore, metabolism-based interactions are likely contributing factors.
Remdesivir is an ester prodrug and undergoes
hydrolysis, most likely by carboxylesterase-1 (CES1). In
addition, remdesivir has a core-structure alanine
(boxed in Figure 1a) as seen with orlistat and sofosbuvir, two covalent inhibitors of CES2.4,5 We therefore
hypothesized that remdesivir irreversibly inhibits CES2.
To test this hypothesis, human liver microsomes pooled
from 23 donors, incubated with remdesivir (0, 0.2 and
1 µmol/L), electrophoretically separated and tested for
the remaining hydrolytic activity in the gel. Electrophoresis removed unbound but not covalently
bound inhibitor, establishing an involvement of
Francßaise de Pharmacologie et de The
ª 2020 Socie
Fundamental & Clinical Pharmacology 35 (2021) 432–434
Potent inhibition of CES2 by remdesivir
Figure 1 Irreversible inhibition of CES2 by remdesivir, and its effect on the hydrolysis of tenofovir disoproxil fumarate (TDF). (a)
Structure of remdesivir (alanine boxed). (b) Native gel electrophoresis stained for hydrolytic activity. Microsomes pooled from 23
individual donors (5 µg) were incubated with remdesivir at 0, 0.2 or 1.0 µmol/L and subjected to native gel electrophoresis stained for
esterase activity with 4-methylumbelliferylacetate, and the staining intensity was captured by Bio-Rad ChemoDoc Imager. (c) Inhibition
of liver microsomal hydrolysis of TDF by remdesivir. Pre-incubation format: pooled liver microsomes (0.06 µg/µL) were pre-incubated at
37°C for 120 min with remdesivir at 0, 0.2 or 1.0 µmol/L followed by TDF at 10 µmol/L. Simultaneous format: pooled liver microsomes
(0.06 µg/µL) were..
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