The acute disposition of (R)- and (s)-methadone in brain and lung of sheep

The cerebral and lung kinetics of the enantiomers of methadone were quantified using a conscious chronically instrumented sheep preparation, as these organs are the major organs governing the peak brain concentrations (and therefore effects) of methadone after ivbolus administration. Seven sheep were administered intravenous infusions of rac-methadone (30 mg over 4 min). Whole blood (R)- and (S)-methadone concentrations were measured using stereoselective HPLC. Methadone transiently increased cardiac output (CO) and mean arterial pressure, but did not alter cerebral blood flow (CBF) or cause significant respiratory depression. Using physiologically based kinetic models, cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and CBF, lung kinetics from pulmonary artery-aortic gradient and CO. Lung and cerebral kinetics were best described by a partially membrane-limited model for both enantiomers. Lung kinetics displayed clear stereoselectivity, due to the smaller apparent volume of the deep lung compartment for (R)-methadone (45 l) compared to (S)-methadone (79 l). This resulted in systemic differences in the concentrations of the enantiomers. Minimal stereoselectivity was observed in cerebral kinetics. The brain:blood equilibration of methadone was slow (half-life of 18 min) due to intermediate permeability and large apparent cerebral distribution volumes. However, the permeability term was sufficiently high that cerebral kinetics were affected by CBF. Simulations demonstrated that if CBF was doubled, the equilibration half-life of methadone with brain tissue decreased by 30%, and there was a 25% increase in the peak brain concentrations. Future studies are needed to confirm the role of cerebral blood flow alterations in the exposure of the brain to methadone, especially in the case of respiratory depression. In conclusion, pharmacokinetic modelling of methadone confirmed a large equilibration delay between brain and blood.