Indirect Parasympathomimetic Activity of Metoclopramide: Reversible Inhibition of Cholinesterases From Human Central Nervous System and Blood

Chemnitius, Jörg-Michael; Haselmeyer, K.H.; Gonska, Bernd–Dieter; Kreuzer, H; Zech, Ronald

doi:10.1006/phrs.1996.9999

Cited by 33 publications

(30 citation statements)

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“…The calculated values are in the low micromolar range indicative of a low affinity of MCP for RBC-AChE. They are consistent with data published by others (Chemnitius et al, 1996). The K values, however, are in a range that is clinically achievable.…”

Section: Discussionsupporting

confidence: 92%

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In vitro protection of red blood cell acetylcholinesterase by metoclopramide from inhibition by organophosphates (paraoxon and mipafox)

Petroianu

Arafat

Kosanović

et al. 2003

J of Applied Toxicology

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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 the human central nervous system and blood, and may have a red blood cell (RBC) acetylcholinesterase (AChE) protective effect against inhibition by organophosphates. The purpose of the study was to quantify 'in vitro', by means of the IC50 shift, the extent of MCP conferred protection, by using paraoxon (POX) and mipafox (MPFX) as inhibitors. Paraoxon is a widely used non-neuropathic organophospate responsible for a large number of accidental or suicidal exposures. Mipafox is a neuropathic organophospate. Red blood cell AChE activities in human plasma were measured photometrically in the presence of different POX, MPFX and MCP concentrations and the IC50 was calculated. Determinations were repeated in the presence of increasing MCP concentrations. It appears that the IC50 shift induced by the presence of MCP increases with the MCP concentration in a linear manner. The protective effect of MCP on cholinesterases could be of practical relevance in the treatment of POX and MPFX poisoning. We conclude that in vivo testing of MCP as an organophosphate protective agent is warranted.

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Section: Discussionsupporting

confidence: 92%

“…As such, MCP is used clinically owing to its prokinetic and antiemetic effects. Prokinetic effects might be enhanced due to an inhibition of the cholinesterase(s) (Graham and Crossley, 1995;Chemnitius et al, 1996). Although the conventional intravenous dose is ca.…”

Section: Introductionmentioning

confidence: 99%

In vitro protection of red blood cell acetylcholinesterase by metoclopramide from inhibition by organophosphates (paraoxon and mipafox)

Petroianu

Arafat

Kosanović

et al. 2003

J of Applied Toxicology

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“…They are consistent with data published by us and others (Chemnitius et al, 1996). Furthermore, the K values are in a range achievable clinically.…”

Section: Discussionsupporting

confidence: 93%

In vitro protection of plasma cholinesterases by metoclopramide from inhibition by mipafox

Petroianu¹,

Kuhn²,

Arafat³

et al. 2004

J of Applied Toxicology

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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.

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“…The D 2 antagonist and 5-HT 4 agonist metoclopramide and the H 2 antagonist ranitidine are widely used in clinical medicine. Besides, both compounds were shown to exhibit weak cholinesterase inhibitory activity (Chemnitius et al, 1996;Sowell et al, 1992;Kosh et al, 1989).…”

Section: Introductionmentioning

confidence: 95%

Effect of metoclopramide and ranitidine on the inhibition of human AChE by VXin vitro

et al. 2005

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The repeated misuse of highly toxic organophosphorus-type (OP) chemical warfare agents ('nerve agents') emphasizes the necessity for the development of effective medical countermeasures. The standard treatment with atropine and acetylcholinesterase (AChE) reactivators ('oximes') is considered to be ineffective with certain nerve agents due to low oxime efficacy. Therefore, pretreatment with carbamate-type compounds, e.g. pyridostigmine, was recommended to improve antidotal efficacy. Recently, the clinically used reversible AChE inhibitors metoclopramide (MCP) and ranitidine (RAN) were shown to exhibit some protective effect against the OP pesticide paraoxon in vitro and in vivo. The present study was undertaken to investigate a potential protective effect of MCP and RAN against inhibition of human AChE by the nerve agent VX (O-ethyl S-[2-(diisopropylamino)ethyl)methylphosphonothioate). Hemoglobin-free human erythrocyte membranes were incubated with various, human relevant MCP (0.5-2 microm) and RAN (0.5-5 microm) concentrations starting 1 min before addition of VX (1-40 nm). Both compounds failed to increase VX IC(50) values. In addition, human AChE was incubated with higher than human relevant therapeutic concentrations of MCP (1 microm-1 mm) and RAN (1 microm-2.0 mm) and inhibited by 40 nm VX. At concentrations higher than 100 microm MCP and RAN caused a concentration dependent increase of residual AChE activity 15 min after addition of VX. These data indicate that MCP and RAN may be ineffective in protecting human AChE against inhibition by the nerve agent VX at human relevant doses.

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Indirect Parasympathomimetic Activity of Metoclopramide: Reversible Inhibition of Cholinesterases From Human Central Nervous System and Blood

Cited by 33 publications

References 0 publications

In vitro protection of red blood cell acetylcholinesterase by metoclopramide from inhibition by organophosphates (paraoxon and mipafox)

In vitro protection of red blood cell acetylcholinesterase by metoclopramide from inhibition by organophosphates (paraoxon and mipafox)

In vitro protection of plasma cholinesterases by metoclopramide from inhibition by mipafox

Effect of metoclopramide and ranitidine on the inhibition of human AChE by VXin vitro

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