Interstitial muscle concentrations of rocuronium under steady-state conditions in anaesthetized dogs: actual versus predicted values

Introduction. The objective of this study was to compare rocuroniumeffect (C_e) and peripheral (C₂) compartment concentrations predictedby pharmacokinetic–pharmacodynamic (PK-PD) modelling withthose measured in plasma (C_p) and in the interstitial fluidof muscle tissue (C_ISF,u) by microdialysis in anaesthetizeddogs. Methods. After approval by the Animal Care Committee, eightadult male dogs with a body weight ranging from 7 to 18 kg wereanaesthetized with pentobarbital. Each dog received a 2-minrocuronium infusion of 0.15 mg kg^–1 min^–1 followedby a 118-min infusion of 60 µg kg^–1 min^–1via the right jugular vein. Arteriovenous gradient across thehindlimb was measured at 40, 60, 100 and 120 min. Three microdialysissamples were collected at 40-min intervals. Once the infusionstopped, arterial samples were collected every 2 min for thefirst 10 min and every 20 min for the next 120 min. Neuromuscularfunction was monitored using train-of-four stimulation untilfull recovery. Dogs were then killed and a biopsy of muscletissue was performed (C_m). Results. At steady state, the mean C_ISF,u value was 1353 ngml^–1. After correction for the unbound fraction in plasma,the mean C_e,corr and C_2,corr were 1681 and 1481 ng ml^–1,respectively. At the terminal sampling point, C_m was 10-foldhigher than C_p. Conclusion. Unbound concentration of rocuronium measured inthe muscle interstitial fluid under steady-state conditionsconfirms that parametric PK-PD modelling gives reliable estimatesof effect site concentrations. Rocuronium accumulates in muscletissue, probably by non-specific protein binding in the interstitialspace.