Weak inhibitors protect cholinesterases from strong inhibitors (paraoxon): in vitro effect of ranitidine

Abstract

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 weak and reversible inhibitor of cholinesterases. We have shown that MCP has a cholinesterase protective effect against inhibition by organophosphates. The putative mode of protective action of MCP is competition for the active site of the enzyme with the more potent organophosphate. In the present paper we present our results using another weak inhibitor of cholinesterases: ranitidine (RAN). The purpose of the study was to quantify in vitro the extent of RAN-conferred protection, using paraoxon (POX) as an inhibitor. Paraoxon is a non-neuropathic organophosphate responsible for a large number of accidental or suicidal exposures. Red blood cell (RBC) acetylcholinesterase (AChE) activities in whole blood and butyrylcholinesterase (BChE) activities in human plasma were measured photometrically in the presence of different POX and RAN concentrations and the IC50 was calculated. Determinations were repeated in the presence of increasing RAN concentrations. The IC50 shift induced by the presence of RAN increases with the RAN concentration in a linear manner. The shift was more pronounced with RBC-AChE. The protective effect of RAN on cholinesterase could be of practical relevance in the treatment of POX poisoning. We conclude that in vivo testing of RAN as an organophosphate protective agent is warranted.