Received for publication March 7, 2006.
Revised June 6, 2006.
Accepted for publication June 7, 2006.

In vivo blood-brain barrier transport of oxycodone in the rat - indications for active influx and implications for PK/PD

Abstract

The blood-brain barrier (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. 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. 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 CL_inand K_p,uu.CL_in describes the clearance of oxycodone across the BBB into the brain, while K_p,uu describes the extent of drug equilibration across the BBB. CL_in across the BBB was estimated to 1910 µL/min·g brain. K_p,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. This is the first evidence of an opioid having an unbound steady-state concentration in brain that is higher than unity, which can explain potency discrepancies between oxycodone and other opioids.

Key words: active transport, blood-brain barrier, blood-CNS transport, CNS pharmacokinetics, computer modeling and simulation, drug efflux, pharmacokinetic modeling, pharmacokinetics, transporters

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