Dose-Dependent Effect of Metoclopramide on Cholinesterases and Suxamethonium Metabolism

Abstract

In obstetric patients undergoing postpartum tubal ligation, we found that metoclopramide produced dose-dependent prolongation of suxamethonium-induced neuromuscular block. Mean block times after suxamethonium 1 mg kg-1 were 8.0 min, 9.83 min and 12.45 min for control and metoclopramide 10 mg and metoclopramide 20 mg groups, respectively. A laboratory study was therefore conducted on the inhibition of human plasma cholinesterase (PCHE) and erythrocyte acetylcholinesterase (ACHE) activity by varying concentrations of metoclopramide using acetylthiocholine as substrate. PCHE showed a greater sensitivity to inhibition by metoclopramide; the concentration of metoclopramide producing 50% inhibition of activity (I50) was 3.16 x 10(-7) mol litre-1, which is within the therapeutic range. ACHE was less sensitive to inhibition by metoclopramide (I50 2.24 x 10(-5) mol litre-1). Analysis of enzyme kinetics at varying substrate concentrations revealed that metoclopramide produced a potent non-competitive, dose-dependent inhibition of both ACHE and PCHE. The inhibition constant, Ki, was 1.88 x 10(-7) mol litre-1 for PCHE and 9.5 x 10(-8) mol litre-1 for ACHE. As metoclopramide is a potent inhibitor of PCHE, interactions might be expected to occur between metoclopramide and drugs that require PCHE for biotransformation, such as suxamethonium and ester local anaesthetics.

The characteristics of the inhibition of serum cholinesterase by metoclopramide

“…This range spans most of the dose response curve for inhibition by metoclopramide. This supports previous observations [5] that metoclopramide can produce a significant prolongation of the action of drugs metabolized by this enzyme. This problem will be most marked in circumstances where the level of enzyme activity is reduced initially [10] such as term pregnancy [11] (Kao [5] showed that in the immidiate post-partum period administration of metoclopramide 20 mg prolongs the duration of action of suxamethonium from 8.0 to 12.5 rain), or where particularly high doses of metoclopramide are used, as in antiemetic therapy for cancer chemotherapy (Graham, Burgess and MacMillan, unpublished data).…”

“…These studies have been conducted using high dilutions of the enzyme source. The enzyme concentrations in vivo are 30-300 times greater than in the cuvette [4][5] competitive, the effective free inhibitor concentrations may be far lower at enzyme concentrations approaching those in vivo. On this basis the previous authors' assumptions that cuvette-derived data would directly reflect in vivo conditions has been questioned [6].…”

“…Structurally it is a substituted benzamide, and a derivative of procainamide. Some benzamides, including procainamide, and local anaesthetic agents, have been shown to inhibit plasma cholinesterase in vitro [1][2][3][4][5]. The nature of such inhibition has been reported to be non-competitive in nature [5].…”

“…On this basis the previous authors' assumptions that cuvette-derived data would directly reflect in vivo conditions has been questioned [6]. Similarly, such assays were undertaken at 25°C, and the kinetics of such a non-competitive interaction might differ at the normal body temperature of 37°C.This work was prompted by the observation that metoclopramide can prolong the duration of action of the normally short acting muscle relaxant suxamethonium [5]. It is possible therefore that the duration of action of other cholinesterase-metabolised drugs such as mivacurium may be similarly prolonged, or the bioactivation of carbamylated prodrugs such as bambuterol reduced by such a drug-enzyme interaction.…”

Levetiracetam, a New Antiepileptic Agent: Lack of In Vitro and In Vivo Pharmacokinetic Interaction with Valproic Acid

“…They were selected, as was their final concentration in the assay, based on the literature: edetic acid (EDTA) and chloromercuribenzoate (1 mM and 100 M, respectively; in-hibitors of A-esterases), paraoxon, physostigmine, metoclopramide, sodium fluoride (NaF), and bis-pnitrophenyl phosphate (BNPP) (all at 100 M; inhibitors of B-esterases), acetazolamide (100 M, inhibitor of carboxylanhydrase), and acetylsalicylic acid (100 M; aspecific inhibitor of esterases) (18)(19)(20)(21)(22)(23). Incubation mixtures contained whole blood (980 l), 700 M LEV (added as 10 l in water), and the inhibitor (added as 10 l in either water or methanol).…”