In vitro protection of plasma cholinesterases by metoclopramide from inhibition by mipafox.
Metoclopramide (MCP) is a dopamine receptor antagonist and serotonin receptor agonist widely used as an antiemetic and gastric prokinetic drug. In addition MCP is a reversible inhibitor of cholinesterases from human central nervous system and blood. Metoclopramide may have a cholinesterase protective effect against inhibition by organophosphates. The purpose of the study was to quantify in vitro, by means of the IC(50) shift, the extent of MCP conferred protection, using mipafox (MPFX) as an inhibitor. Mipafox is a neuropathic organophosphate. Cholinesterase activities (with acetylthiocholine [ChE-A] and butyrylthiocholine [ChE-B] as substrates) in human plasma were measured photometrically in the presence of different MPFX concentrations and the IC(50) was calculated. Determinations were repeated in the presence of increasing MCP concentrations. It appears that the shift induced by the presence of MCP increases with the MCP concentration in a linear manner. In the presence of a clinically easily achievable plasma concentration of 1 micro M MCP, the IC(50) of MPFX for cholinesterase 'shifts' by a factor of ca. 3-6. The protective effect of MCP on cholinesterase could be of practical relevance in the treatment of organophosphate poisoning. We conclude that in vivo testing of MCP as an organophosphate protective agent is warranted.
Petroianu
G
G
United Arab Emirates University, Department of Pharmacology and Therapeutics, PO Box 17666, Al Ain, United Arab Emirates. georg.petroianu@uaeu.ac.ae
Kühn
F
F
Arafat
K
K
Zuleger
K
K
Missler
A
A
D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002802:Cholinesterases / Q000097:blood*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007531:Isoflurophate / Q000031:analogs & derivatives* / Q000633:toxicity*; D008787:Metoclopramide / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D018492:Dopamine Antagonists; D007531:Isoflurophate; C005238:mipafox; D002802:Cholinesterases; D008787:Metoclopramide