Abstract
Purpose:
A virtual screening study has suggested that the skeletal muscle relaxant, dantrolene,
and the antiemetic drug, ondansetron, may act as inhibitors of the enzyme acetylcholinesterase
(AChE). Based on this proposal, the current study examines the AChE inhibitory properties
of these drugs.
Methods and Findings:
Using AChE from human erythrocytes as enzyme source, it is shown that dantrolene and
ondansetron inhibit AChE with IC50 values of 12.8 µM and 37.1 µM, respectively. For comparison, the reference AChE inhibitors,
tacrine and ranitidine, exhibit IC50 values of 0.144 µM and 3.37 µM, respectively. By measuring the recoveries of enzyme
activities after dilution of enzyme-inhibitor mixtures, it is further shown that dantrolene
and ondansetron act as reversible AChE inhibitors.
Conclusions:
By considering the typical plasma concentrations of dantrolene and ondansetron in
humans at therapeutic doses, the pharmacological relevance of the AChE inhibitory
potencies of these drugs is discussed. At typical plasma concentrations, ondansetron
is unlikely to inhibit AChE under physiological conditions. The inhibition of AChE
by ondansetron is therefore not of clinical relevance in humans. In contrast, after
intravenous administration of dantrolene to humans, the typical plasma concentrations
reached are similar to the recorded IC50 value for the inhibition of AChE, and dantrolene may thus produce pharmacological
significant inhibition of AChE. Further investigation is necessary to clarify the
pharmacological relevance of the AChE inhibitory effect of dantrolene.
Key words
acetylcholinesterase - dantrolene - ondansetron - inhibition - ondansetron
