Pharmacokinetics of ketamine following a short intravenous infusion to isoflurane-anesthetized New Zealand White rabbits (Oryctolagus cuniculus)

Abstract

ObjectiveTo describe the pharmacokinetics of ketamine following a short intravenous (IV) infusion to isoflurane-anesthetized rabbits. Study designProspective experimental study. AnimalsA total of six adult healthy female New Zealand White rabbits. MethodsAnesthesia was induced with isoflurane in oxygen. Following determination of isoflurane minimum alveolar concentration (MAC), the isoflurane concentration was reduced to 0.75 MAC and ketamine hydrochloride (5 mg kg–1) was administered IV over 5 minutes. Blood samples were collected before and at 2, 5, 6, 7, 8, 9, 13, 17, 21, 35, 65, 125, 215 and 305 minutes after initiating the ketamine infusion. Samples were processed immediately and the plasma separated and stored at –80 °C until analyzed for ketamine and norketamine concentrations using liquid chromatography–mass spectrometry. Compartment models were fitted to the concentration–time data for ketamine and for ketamine plus norketamine using nonlinear mixed-effects (population) modeling. ResultsA three- and five-compartment model best fitted the plasma concentration–time data for ketamine and for ketamine plus norketamine, respectively. For the ketamine only model, the volume of distribution at steady state (Vss) was 3217 mL kg–1, metabolic clearance was 88 mL minute–1 kg–1 and the terminal half-life was 59 minutes. For the model including both ketamine and norketamine, Vss were 3224 and 2073 mL kg–1, total metabolic clearance was 107 and 52 mL minute–1 kg–1 and terminal half-lives were 52 and 55 minutes for the parent drug and its metabolite, respectively. Conclusions and clinical relevanceThis study characterized the pharmacokinetics of ketamine and norketamine in isoflurane-anesthetized New Zealand White rabbits following short IV infusion. The results obtained herein will be useful to determine ketamine infusion regimens in isoflurane-anesthetized rabbits.