Blood-brain equilibration kinetics of levo-alpha-acetyl-methadol using a chronically instrumented sheep preparation

Abstract

The delayed onset and long duration of action of the opioid agonist levo--acetyl-methadol (LAAM) has been attributed to the formation of active metabolites. However, at present, little is known about the time course of blood–brain equilibration of LAAM itself. The cerebral kinetics of LAAM were quantified using physiologically based kinetic models and a conscious chronically instrumented sheep preparation. Seven sheep were administered 4 min intravenous infusions of 30 mg LAAM. Concentrations of LAAM and N-demethylated metabolites (nor-LAAM and di-nor-LAAM) in whole blood (0–75 min) were measured using a validated HPLC assay. LAAM did not alter cerebral blood flow, mean arterial pressure or cause significant respiratory depression. Cardiac output was similar to baseline at 4 min, but decreased by 30% at 10 min and remained at this level for the duration of the 75 min study period. Cerebral kinetics were best described by a membrane-limited model, with a relatively slow blood–brain tissue equilibration half-life of 22 min due to intermediate permeability (56 ml min-1) and a large cerebral distribution volume (724 ml). In conclusion, pharmacokinetic–pharmacodynamic modelling of LAAM should account for the large equilibration delay between brain and blood caused by slow equilibration kinetics. This may account for some of the delay in onset of effect previously attributed to the delayed appearance of active metabolites in blood.