Involvement of nucleophiles in the inactivation of atracurium

Atracurium was incubated in 0.9% sodium chloride solution at pH 7.4 and 37 degrees C. The following compounds were added to the incubation solution: propionic acid, alanine and cysteine (0.1 mol litre-1 final concentration). Metocurine was also incubated with cysteine under identical conditions. Aliquots of the incubation solutions were injected i.v. to anaesthetized rats at the start (0 min) and at the end of incubation (45 min), and the indirectly elicited, single twitches of the gastrocnemius muscle were observed. Whereas inactivation of atracurium proceeded slowly in the control solution and in the presence of sodium propionate, the presence of alanine and, especially, of cysteine markedly enhanced the inactivation. Incubation of metocurine with cysteine did not alter the pharmacological responses. The concentration of cysteine decreased progressively during its incubation with atracurium (37 degrees C, pH 7.4). We conclude that the data are compatible with the postulate that a nucleophile may enhance the degradation of atracurium by a reaction with the parent compound (nucleophilic substitution reaction), by reaction with acrylates (Michael addition) or both.