In vivo blood-brain barrier transport of oxycodone in the rat – active influx and implications for PK/PD
Boström, Emma, Ulrika S. H. Simonsson and Margareta Hammarlund-Udenaes
Division of Pharmacokinetics and Drug Therapy, Department of Biopharmaceutical Sciences, Box 591, 751 24 Uppsala, Sweden
Objectives: Brain distribution can be described with respect to the rate and extent of equilibration of a drug molecule across the blood-brain barrier (BBB) (1). The rate of equilibrium can be expressed as clearances into and out of the brain, CLin and CLout, respectively. The extent of equilibration across the BBB can be expressed as the ratio of the steady-state concentration of unbound drug in brain over unbound drug in blood, Kp,uu (2). Conclusions on the bidirectional transport properties of the BBB can be drawn based on the unbound concentrations in brain and blood (3).
Methods: In this study, the BBB transport of oxycodone was studied in rats. Microdialysis probes were inserted into the striatum and vena jugularis. Ten animals were given a bolus dose followed by a 120 minute constant rate infusion to study the steady-state concepts of oxycodone BBB equilibration. Another ten animals were given a 60 minute constant rate infusion to study the rate of equilibration across the BBB. Microdialysates and plasma samples were collected for 240 minutes from the start of the infusions. Oxycodone-D3 was used as a calibrator for the microdialysis experiments. The samples were analyzed with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and a population pharmacokinetic model was used to simultaneously fit all the data using NONMEM.
Results: A two-compartment model which allowed for a delay between the venous and arterial compartments best described the pharmacokinetics for oxycodone in blood and plasma, while a one-compartment model was sufficient to describe the pharmacokinetics in the brain. The BBB transport of oxycodone was parameterized as CLin and Kp,uu. CLin across the BBB was estimated to 1910 μL/min·g brain. Kp,uu was estimated to 3.0, meaning that the unbound concentration of oxycodone in brain was 3 times higher than in blood, which is an indication of active influx of oxycodone at the BBB.
Conclusion: This is the first evidence of an opioid having an unbound steady-state concentration in brain that is higher than in blood. Other opioids have much lower ratios, the Kp,uu for morphine was for example 0.29 (4). The observation of a Kp,uu for oxycodone greater than unity might explain the equi-analgesic potency of oxycodone and morphine in vivo, in spite of the much weaker µ-receptor affinity of oxycodone compared to morphine.
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