S Ezzine1, F Varin. 1. Faculté de pharmacie, Université de Montréal, Montréal, Québec, Canada.
Abstract
INTRODUCTION: The objective of this study was to compare rocuronium effect (C(e)) and peripheral (C(2)) compartment concentrations predicted by pharmacokinetic-pharmacodynamic (PK-PD) modelling with those measured in plasma (C(p)) and in the interstitial fluid of muscle tissue (C(ISF,u)) by microdialysis in anaesthetized dogs. METHODS: After approval by the Animal Care Committee, eight adult male dogs with a body weight ranging from 7 to 18 kg were anaesthetized with pentobarbital. Each dog received a 2-min rocuronium infusion of 0.15 mg kg(-1) min(-1) followed by a 118-min infusion of 60 microg kg(-1) min(-1) via the right jugular vein. Arteriovenous gradient across the hindlimb was measured at 40, 60, 100 and 120 min. Three microdialysis samples were collected at 40-min intervals. Once the infusion stopped, arterial samples were collected every 2 min for the first 10 min and every 20 min for the next 120 min. Neuromuscular function was monitored using train-of-four stimulation until full recovery. Dogs were then killed and a biopsy of muscle tissue was performed (C(m)). RESULTS: At steady state, the mean C(ISF,u) value was 1353 ng ml(-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-fold higher than C(p). CONCLUSION: Unbound concentration of rocuronium measured in the muscle interstitial fluid under steady-state conditions confirms that parametric PK-PD modelling gives reliable estimates of effect site concentrations. Rocuronium accumulates in muscle tissue, probably by non-specific protein binding in the interstitial space.
INTRODUCTION: The objective of this study was to compare rocuronium effect (C(e)) and peripheral (C(2)) compartment concentrations predicted by pharmacokinetic-pharmacodynamic (PK-PD) modelling with those measured in plasma (C(p)) and in the interstitial fluid of muscle tissue (C(ISF,u)) by microdialysis in anaesthetized dogs. METHODS: After approval by the Animal Care Committee, eight adult male dogs with a body weight ranging from 7 to 18 kg were anaesthetized with pentobarbital. Each dog received a 2-min rocuronium infusion of 0.15 mg kg(-1) min(-1) followed by a 118-min infusion of 60 microg kg(-1) min(-1) via the right jugular vein. Arteriovenous gradient across the hindlimb was measured at 40, 60, 100 and 120 min. Three microdialysis samples were collected at 40-min intervals. Once the infusion stopped, arterial samples were collected every 2 min for the first 10 min and every 20 min for the next 120 min. Neuromuscular function was monitored using train-of-four stimulation until full recovery. Dogs were then killed and a biopsy of muscle tissue was performed (C(m)). RESULTS: At steady state, the mean C(ISF,u) value was 1353 ng ml(-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-fold higher than C(p). CONCLUSION: Unbound concentration of rocuronium measured in the muscle interstitial fluid under steady-state conditions confirms that parametric PK-PD modelling gives reliable estimates of effect site concentrations. Rocuronium accumulates in muscle tissue, probably by non-specific protein binding in the interstitial space.