Dose-dependent pharmacokinetics of ropivacaine in anesthetized rabbits : absence of changes in protein binding

Abstract

Objective: The primary objectives of this study were to investigate the in vivo pharmacokinetics and in vitro plasma protein binding of ropivacaine at the concentration range observed after intravenous administration of different doses in anesthetized rabbits. Study design: Prospective experimental study Animals: Thirteen New Zealand White rabbits Methods: Rabbits were anesthetized with isoflurane. Different doses (0.62 to 6.52 mg/kg) of 0.5 % plain ropivacaine hydrochloride were administered and arterial blood sampled at frequent intervals up to 10 hours. Ropivacaine plasma concentrations were determined by high performance liquid chromatography. Pharmacokinetic analysis of individual data sets was performed using non-compartmental approach to calculate area under the plasma concentration–time curve from time zero to infinity (AUC0–inf). In vivo pharmacokinetics linearity was verified using analyses of variance for between group comparisons of the effect of dose on the AUC0–inf normalized by the dose. A population pharmacokinetic model was developed to describe ropivacaine disposition after intravenous administration in the linear range of dose in anesthetized rabbits. Determination of protein binding was performed, under controlled temperature and pH conditions, in plasma samples spiked extemporaneously with 3 H-ropivacaine and unlabeled ropivacaine (2.5 and 3500 ng/ml) using an ultrafiltration method. Results: At intravenous doses higher than 3.67 mg/kg, dose-dependent changes in ropivacaine systemic clearance were observed. In contrast, protein binding was found to be concentration independent in the tested range. Conclusions and clinical relevance: In anesthetized rabbits, saturation of ropivacaine plasma protein binding is not the mechanism responsible for the pharmacokinetic nonlinearity of ropivacaine observed at intravenous doses higher than 3.67 mg/kg. Disposition parameters obtained in our study will enable accurate characterization of ropivacaine pharmacokinetics after a peripheral nerve block.