Inactivation of atracurium in human and rat plasma.
The contribution of enzyme-catalyzed hydrolysis to inactivation of atracurium in human and rat plasma was determined in vitro by inhibiting the enzyme carboxylesterase with triorthotolyl phosphate. The inhibitor was removed by centrifugation and aspiration. Atracurium was then added to both the control and the inhibited plasma samples, and all samples were incubated at 37 degrees C for 45 min. The amount of atracurium present in aliquots of plasma was determined using a bioassay technique in anesthetized rats. Inactivation of atracurium proceeded rapidly in control rat plasma but was markedly slowed in samples treated with the inhibitor of carboxylesterase. In contrast, the inactivation was slow in control human plasma, and inhibition of carboxylesterase produced only marginal, if any, effects. We conclude that the inactivation of atracurium proceeds, in part, by enzyme-catalyzed ester hydrolysis. In species with high enzyme activity in plasma, e.g., the rat, enzyme-catalyzed hydrolysis is clearly evident. In humans, the level of enzyme activity is low and the contribution of enzyme-catalyzed inactivation is less manifest. By exclusion, Hofmann elimination or other reactions probably represent the major inactivation pathway in humans.
Nigrovic
V
V
Pandya
J B
JB
Auen
M
M
Wajskol
A
A
D000818:Animals; D001279:Atracurium; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000097:blood; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D007546:Isoquinolines / Q000097:blood* / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D003473:Neuromuscular Nondepolarizing Agents / Q000097:blood* / Q000494:pharmacology; D051381:Rats; D014317:Tritolyl Phosphates / Q000494:pharmacology
D007546:Isoquinolines; D003473:Neuromuscular Nondepolarizing Agents; D014317:Tritolyl Phosphates; D001279:Atracurium; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; C025541:tri-o-cresyl phosphate