In vitro microsomal metabolism of imipramine under conditions mimicking thein vivo steady-state situation

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Abstract
A steady‐state model is presented of the metabolism of imipramine. In this model, the N‐demethylation and 2‐hydroxylation rates of imipramine were measured with and without the presence of metabolites by using a tritium isotope of imipramine. At an imipramine concentration of 5 μmol/l, desipramine, in the concentration ratio 1:2, decreased the total metabolic rate by 70%. The 2‐hydroxylation pathway was mainly inhibited, thereby increasing the N‐demethylation pathway from 25% to 62% in the presence of desipramine. The additional presence of 2‐hydroxy‐imipramine did not change this situation. A study on the relative influence of CYP1A2 and 3A4 only revealed minor changes in the presence of desipramine. In conclusion, the presence of metabolites in metabolism studies undertaken in vitro may reflect the changes from the single‐ to the multiple‐dose situation observed clinically and therefore constitute a better model for the clinical application of a drug. Copyright © 2004 John Wiley & Sons, Ltd.

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