Effect of thioridazine on the first-pass kinetics of [¹⁴C]imipramine in perfused rat liver: interaction at hepatic binding sites

Abstract

1. The effect of thioridazine on the first-pass removal and hepatic metabolism of [¹⁴C]imipramine was examined in a single-pass rat liver perfusion system using a perfusate free of drug-binding components. Drug exposure continued for 45min, and bile was collected and analysed during the final 15min when approx. steady-state conditions were attained.

2. Thioridazine decreased the hepatic extraction ratio for imipramine, lowered the hepatic concentration (P< 0.1) and increased the effluent perfusate-to-liver ratios of imipramine. It is suggested that the increased imipramine in the effluent perfusate was due to competition of thioridazine for non-metabolizing binding sites in the liver rather than to inhibition of drug metabolism.

3. Thioridazine markedly increased desipramine concentrations in both liver and effluent perfusate. This may have resulted from decreased hepatic binding of imipramine, which made more free drug available for demethylation. Competition with thioridazine for hepatic binding sites also explains the increased diffusion of desipramine into the effluent perfusate.

4. Lower concentrations of 2-hydroxylated metabolites, especially 2-hydroxyimi-pramine, were found in bile when thioridazine was administered with imipramine. There was no evidence of inhibition of imipramine 2-hydroxylation. From bile-to-liver ratios, it is suggested that thioridazine and/or its metabolites inhibits glucuronylation of 2-hydroxy-imipramine but not of 2-hydroxydesipramine.