ATRACURIUM DECAY AND THE FORMATION OF LAUDANOSINE IN HUMANS

Several groups of investigators have reported that the plasma concentrations of laudanosine, a metabolite of atracurium, are high immediately after administration of atracurium and thereafter decline. Such a time profile of a metabolite in plasma is very unusual. The authors describe a model of atracurium decay and laudanosine disposition that satisfactorily explains these data. The model reveals the following: 1) each atracurium molecule is degraded into two of laudanosine; 2) the generation of laudanosine occurs through two processes-a rapid one, involving approximately 31% of the atracurium dose and proceeding with a half-life of 0.25 min, and a slower one, involving the residual 69% and proceeding with a half-life of 51 min; 3) atracurium degradation by Hofmann elimination proceeds in the central and the noncentral compartments; 4) laudanosine formed from atracurium gains access to its central compartment and disappears from plasma in a biexponential pattern; 5) in cirrhotic patients, only 18% of the atracurium dose is degraded rapidly and laudanosine is disposed of more slowly. The authors propose that the rapid degradation of atracurium in plasma proceeds through a nucleophilic substitution reaction, with plasma nucleophiles substituting for the laudanosine moiety in atracurium. Because both laudanosine moieties in atracurium are required to establish and sustain plasma concentrations of laudanosine, excretion of atracurium or its degradation through pathways not generating laudanosine must be small.