Abstract
Cytotoxicity of atracurium and of its metabolites was tested in vitro.Exposure of isolated rat hepatocytes to atracurium produced cellular damage evidenced by extrusion of an intracellular enzyme, lactate dehydrogenase (LDH), into the incubation medium. Leakage of LDH was directly related to the concentration of atracurium in the medium (250 to 800 μM). If the spontaneous degradation of atracurium (presumably via Hofmann elimination) was first carried out in vitroand the degradation products subsequently added to the isolated hepatocytes, the leakage of LDH was also dose-dependent but larger than that observed after the addition of the parent drug. When l-cysteine was admixed to the products of the spontaneous degradation of atracurium prior to their addition to the liver cells, no leakage of LDH was observed. The results are compatible with the working hypothesis that atracurium itself and, even more so, acrylates formed in Hofmann elimination of atracurium, are reactive toward nucleophiles and damage the cells by alkylating nucleophiles present in cellular membranes. Antecedent covalent binding of acrylates to the nucleophile cysteine, i.e., the formation of acrylatecysteine adducts, saturated the reactive capacity of acrylates for nucleophiles and thus prevented the reactive metabolites from alkylating the endogenous nucleophiles. Possible clinical consequences resulting from in vivogeneration of reactive metabolites are not clear at the present time but are projected to be related to (a) the dose of atracurium administered, (b) the amount of acrylates generated, (c) the functional importance of the endogenous nucleophiles alkylated, and (d) the pathway and the speed of detoxification of atracurium and its metabolites.
Résumé
La cytotoxicité de l’atracurium et de ses métabolites a été éudiée in vitro.L’exposition d’hépatocytes de rat à l’atracurium a produit des dommages cellulaires tel qu ’ exprime par la libération de déhydrogénase lactique (LDH), dans le médium d’incubation. La quantite de LDH libérée était directement reliée à la concentration de l’atracurium dans le médium (250 à 800 μM). Après dégradation de l’atracurium in vitroet addition des produits de la dégradation aux hépatocytes, la libération du LDH était aussi dépendante de la dose mais bien superieure à celle observée après l’addition de l’atracurium lui-même. Quand la l-cystéine a été additionnée au produit de degradation de l’atracurium avant de les présenter aux hépatocytes, aucune libération de LDH ne fut observée. Ces résultats sont compatibles avec l’hypothese que l’ atracurium elle-même ainsi que ses métabolites sont réactives sur les nucléophiles et peuvent endommager les cellules. L’addition de L-cystéïne a atténué l’qffinité des acrylates pour les nucléophiles et a prévenu ainsi le dommage cellulaire. Les conséquences cliniques possibles de cette génération in vivode métabolites réactifs ne sont pas encore élucidées mais peuvent être la conséquence de (a) la dose d’atracurium administrée, (b) la quantité d’acrylates générée, (c) l’importance fonctionnelle des nucléophyles endogènes alkylés, et (d) la voie et la vitesse de détoxification de l’atracurium et de ses métabolites.
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Nigrovic, V., Pandya, J.B., Klaunig, J.E. et al. Reactivity and toxicity of atracurium and its metabolitesin vitro . Can J Anaesth 36, 262–268 (1989). https://doi.org/10.1007/BF03010762
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DOI: https://doi.org/10.1007/BF03010762