Determination of plasma and brain concentrations of SCH 39166 and their correlation to conditioned avoidance behavior in rats

Plasma and brain concentrations of the dopamine D₁ receptor antagonist, SCH 39166, were measured and compared to behavioral activity in the conditioned avoidance response paradigm (CAR). SCH 39166 was administered at two behaviorally active doses (1 mg/kg, SC and 10 mg/kg, PO) and the time course for CAR activity was compared with the plasma and brain concentrations of unconjugated SCH 39166. Conjugation andN-demethylation of SCH 39166 after oral administration were also determined and first pass metabolism examined. Results from these studies demonstrated a similar time-dependent disappearance of unconjugated SCH 39166 from both the plasma and brain, independent of route of administration. Brain concentrations of SCH 39166 were approximately 5-fold higher than corresponding plasma concentrations, regardless of route. However, plasma and brain concentrations of unconjugated SCH 39166 were higher after SC administration of 1.0 mg/kg, than after PO administration of 10 mg/kg, suggesting a substantial first pass metabolism of SCH 39166. In addition, total (conjugated and unconjugated) plasma concentrations of SCH 39166 were at least 10-fold higher than unconjugated concentrations of SCH 39166 after PO administration of 10 mg/kg, demonstrating that a high proportion of drug was conjugated. Metabolism to theN-desmethyl analog, SCH 40853, was observed after PO administration of 10 mg/kg SCH 39166 and a high proportion of conjugation of the desmethyl analog was also seen. Finally, plasma concentrations of unconjugated SCH 39166 exhibited a high positive correlation (r=0.934,P<0.001) with brain concentrations of unconjugated SCH 39166. Behavioral activity in the CAR was also positively correlated with plasma concentrations (r=0.95,P<0.001) and brain concentrations (r=0.88,P<0.001) of unconjugated SCH 39166.