Enzymatic hydrolysis of atracurium in vivo

Inactivation of atracurium in vivo has been postulated to proceed along two pathways: Hofmann elimination and ester hydrolysis. Since an end product of Hofmann elimination (acrylate) may be potentially toxic, the authors conducted a study to determine the extent of degradation via enzyme-catalyzed hydrolysis relative to that via Hofmann elimination. The enzyme carboxylesterase was inhibited by the pretreatment of rats with an organophosphorous compound, triorthotolyl phosphate (TOTP). Skeletal muscle relaxation produced either by d-tubocurarine or succinylcholine was not influenced by the pretreatment. This indicates that TOTP does not alter directly the paralyzing properties of either depolarizing or nondepolarizing muscle relaxants. Relaxation produced by atracurium, however, was prolonged markedly and the rate of recovery from relaxation was decreased. The authors conclude: 1) enzyme-catalyzed hydrolysis is probably responsible for the short duration of action of atracurium; 2) Hofmann elimination, at least in rats, probably is not the principal degradation pathway; and 3) the opportunity for in vivo generation of large amounts of potentially toxic end products is less than previously implied.