Pharmacokinetics of fentanyl after single intravenous injection and constant rate infusion in dogs

Objective: To determine the plasma concentration and define the pharmacokinetic characteristics of fentanyl (10 μg kg^-1) administered as a single intravenous (IV) injection followed by: (a) no further drug; or (b) a constant rate infusion (CRI) of fentanyl 10 μg kg^-1 hour^-1 lasting 1, 3 or 4 hours in dogs. Animals: Fourteen healthy adult beagles (seven males and seven females). Experimental design: Randomized cross-over design. Materials and methods: Dogs were randomly assigned to four treatment groups. Drugs were administered to each dog in a randomized cross-over design with at least a 14-day washout interval between experiments. All dogs received an IV loading dose of fentanyl (10 μg kg^-1). One group received no further fentanyl. In others, the loading dose was followed by a CRI of fentanyl (10 μg kg^-1 hour^-1) for 1, 3 or 4 hours. Blood samples were collected and plasma fentanyl concentrations determined using high-performance liquid chromatography-mass spectrometry. Plasma pharmacokinetic estimates were obtained by plotting plasma concentrations versus time data and by fitting the change in concentration to a pharmacokinetic model, using a purpose-built program written by the Graduate School of Pharmaceutical Sciences (Kyoto University) in Visual Basic (VBA) on Excel (Microsoft Corporation). Results: Plasma fentanyl concentration decreased rapidly after single IV injection: the plasma concentration-time curve best fitted a two-compartment model. Pharmacokinetic variables for IV injection were characterized by a short distribution half-time (t_1/2α was 4.5 minutes), a relatively long elimination half time (t_1/2β was 45.7 minutes), a large volume of distribution (approximately 5 L kg ^-1) and high total body clearance (77.9 mL minute^-1 kg^-1). Stable plasma fentanyl levels were obtained in all CRI groups although pharmacokinetic variables were influenced by the duration of administration. Conclusions and clinical relevance: While this study clarified the pharmacokinetic features of rapid IV fentanyl injection and CRI in dogs, the plasma concentration achieving analgesia was not and so further research is needed. Further studies on the effects of other sedatives and/or anaesthetics on fentanyl's disposition are also required as the drug is commonly used with other agents.