Reversal of neuromuscular blockade and simultaneous increase in plasma rocuronium concentration after the intravenous infusion of the novel reversal agent Org 25969.
BACKGROUND
The purpose of this study was to determine the changes in the plasma concentration of rocuronium and the reversal of its neuromuscular blockade after the intravenous infusion of Org 25969, the novel neuromuscular block-reversal agent, in anesthetized guinea pigs.


METHODS
Rocuronium was infused for 1 h at a rate of 12-19 nmol.kg-1.min-1 to produce a steady-state 90% neuromuscular block. After 30 min, a concomitant infusion of either the reversal agent Org 25969 at a rate of 50 nmol.kg-1.min-1 or an infusion of an equivalent volume of saline was started. The time course of plasma concentrations of rocuronium was determined by use of liquid chromatography-mass spectrometry/mass spectrometry.


RESULTS
In both treatment groups, a steady-state plasma concentration of rocuronium was obtained after 30 min. In the saline-treated group, the plasma concentration of rocuronium and depth of block remained constant. In the Org 25969 group, neuromuscular block was reversed while the rocuronium infusion was ongoing. Simultaneously, an increase in the total plasma concentration of rocuronium (free and complexed) was observed, even though the infusion rate of rocuronium was not changed. Compared with the saline-treated group, a small increase in the postmortem bladder concentration of rocuronium was detected.


CONCLUSIONS
The authors propose that the capture of rocuronium by Org 25969 causes the rapid reversal of neuromuscular block. The reversal can be explained by the rapid transfer of free rocuronium from the effect compartment (neuromuscular junction) to the central compartment, in which it is bound to Org 25969. This explains the increase in total plasma concentration of rocuronium (free and bound to Org 25969).
Epemolu
Ola
O
Department of Pharmacology, Organon Research, Scotland, United Kingdom. o.epemolu@organon.co.uk
Bom
Anton
A
Hope
Frank
F
Mason
Rona
R
D000732:Androstanols / Q000037:antagonists & inhibitors* / Q000097:blood* / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000008:administration & dosage / Q000494:pharmacology*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D013058:Mass Spectrometry; D009119:Muscle Contraction / Q000187:drug effects; D003473:Neuromuscular Nondepolarizing Agents / Q000037:antagonists & inhibitors* / Q000097:blood* / Q000494:pharmacology; D014677:Pharmaceutical Vehicles; D000077123:Rocuronium; D000077122:Sugammadex; D047408:gamma-Cyclodextrins
D000732:Androstanols; D003505:Cyclodextrins; D003473:Neuromuscular Nondepolarizing Agents; D014677:Pharmaceutical Vehicles; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D000077123:Rocuronium