Imipramine Kinetics in the Single Pass Rat Liver Perfusion Model

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Abstract
Imipramine [a tricyclic antidepressant] elimination and metabolism was studied in a single-pass rat liver perfusion model with flow and pressure kept constant for a perfusion-period of 120-200 min. Imipramine was eliminated from the liver mainly in 3 ways: unchanged in the outflow medium, by demethylation forming desipramine, and by 2-hydroxylation and subsequent glucoronide coupling. The formed desipramine was eliminated unchanged (outflow) or by 2-hydroxylation + glucuronide coupling. The conjugated metabolites were mainly eliminated via the bile. By perfusion with constant imipramine concentration in the inflow medium (10-50 .mu.M), steady state could not be obtained within 120 min/perfusion time, neither in terms of a constant outflow concentration, nor in terms of balance between input and output. Perfusion with imipramine for 20 min/(single-dose) followed by perfusion with drug-free medium showed an extensive elimination of imipramine (extraction ratio 0.64-0.97) and rapid disappearance of imipramine from outflow medium t(1/2 [half-life] 5-10 min). A 2nd single dose imipramine perfusion given 70-90 min after start showed a significant reduction in extraction ratio. At the same time the elimination via bile decreased about 50%, and only a fraction of this decrease was accounted for by a decrease in bile flow. A gradual decline in elimination rate may explain the difficulties in reaching a steady state during constant infusion with imipramine. Gradual changes in distribution kinetics could not be excluded. Results of both types of experiments (continuous or single dose administration) indicated dose dependent elimination compatible with saturation kinetics.

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