Antagonism of vecuronium by one of its metabolites in vitro.

The neuromuscular-blocking agent vecuronium bromide undergoes hydrolysis to three pharmacologically active metabolites (3-desacetyl, 17-desacetyl and 3,17-desacetyl vecuronium) which might modify the neuromuscular-blocking action of their parent compound. In order to elucidate the possible role of the interaction between vecuronium and its metabolites in the complications reported after long-term use of vecuronium in intensive care unit (ICU) patients, the relative potency of vecuronium, 3-desacetyl and 3,17-desacetyl vecuronium was determined in the rat hemidiaphragm in vitro and the mode of interaction of the above-mentioned compounds investigated. Dose-response relationships were established for each substance alone and for combinations of vecuronium with its metabolites. The relative potency at the EDmax50 levels (% maximal effect) were in the order of 1:1.2:27 for vecuronium, the 3-desacetyl derivative and the 3,17-desacetyl derivative, respectively. The mode of interaction characterized by isobolographic and algebraic (functional) analysis showed vecuronium and 3-desacetyl vecuronium to interact in an additive fashion while the combined effect of the parent compound and its 3,17-desacetyl derivative was less than additive, indicating antagonism.