Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model

Abstract

The pharmacokinetics and time course of blood–brain equilibration of buprenorphine (BUP) and norbuprenorphine (norBUP) in sheep were characterized. Sheep were administered 0.04 mg kg⁻¹ BUP or 0.6 mg kg⁻¹ norBUP as 4-min i.v. infusions. The cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and changes in cerebral blood flow. These data were fitted to physiologically based pharmacokinetic models. BUP cerebral kinetics were best described by a membrane-limited model with a large equilibration delay (half-life of 20 min) between brain and blood due to intermediate permeability (47 ml min⁻¹) and a large cerebral distribution volume (595 ml). Significant limitation in permeability (6 ml min⁻¹) characterized the cerebral kinetics of norBUP with a cerebral distribution volume (157 ml) giving a blood–brain equilibration half-life (21 min) similar to that for BUP. The logD of BUP and norBUP were 3.93 ± 0.08 and 1.18 ± 0.04 (mean ± SD), respectively. Both compounds revealed slow cerebral equilibration with variations in degree of permeability and distribution volume reflecting the difference in lipophilicity. It is possible that norBUP contributes to the central effects seen after chronic BUP administration as this study demonstrated its entry into the brain.

Key Words::

• Buprenorphine
• norbuprenorphine
• CNS distribution
• physiologically based pharmacokinetics
• blood–brain barrier

Acknowledgements

The authors thank Tasmanian Alkaloids (Westbury, Tasmania, Australia) for providing the norbuprenorphine HCl. This work was supported by the National Health and Medical Research Council of Australia (Project Grant 157942).