The inhibition of acetylcholinesterase by dantrolene and ondansetron.
OBJECTIVE
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.


RESULTS
Using AChE from human erythrocytes as enzyme source, it is shown that dantrolene and ondansetron inhibit AChE with IC(50) values of 12.8 µM and 37.1 µM, respectively. For comparison, the reference AChE inhibitors, tacrine and ranitidine, exhibit IC(50) 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 IC(50) 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.
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa.
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Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Potchefstroom, South Africa.
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Petzer
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa.
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JP
Petzer
D000932:Antiemetics / Q000008:administration & dosage / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D003620:Dantrolene / Q000008:administration & dosage / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D009125:Muscle Relaxants, Central / Q000008:administration & dosage / Q000494:pharmacology; D017294:Ondansetron / Q000008:administration & dosage / Q000494:pharmacology*; D011899:Ranitidine / Q000008:administration & dosage / Q000494:pharmacology; D013619:Tacrine / Q000008:administration & dosage / Q000494:pharmacology
D000932:Antiemetics; D002800:Cholinesterase Inhibitors; D009125:Muscle Relaxants, Central; D017294:Ondansetron; D013619:Tacrine; D011899:Ranitidine; D003620:Dantrolene