Effect of ketoconazole on the pharmacokinetics of imipramine and desipramine in healthy subjects

Aims The aim of the study was to characterize further the role of CYP3A4 in the metabolism of tricyclic antidepressants.

Methods The effect of oral ketoconazole (200 mg day(-1) for 14 days) on the kinetics of a single oral dose of imipramine (100 mg) and desipramine (100 mg) was evaluated in two groups of six healthy male subjects.

Results Ketoconazole administration was associated with a decrease in imipramine apparent oral clearance (from 1.16 +/- 0.21 to 0.96 +/- 0.20 l h(-1) kg(-1) mean +/- s.d.; P<0.02), a prolongation in imipramine half-life (from 16.7 +/- 3.3 to 19.2 +/- 5.4 h, P<0.05) and a decrease in area under the curve of metabolically derived desipramine (from 3507 +/- 1707 to 3180 +/- 1505 nmol l(-1) h, P<0.05), whereas concentrations of 2-hydroxy-imipramine were unaffected. In the subjects given desipramine, no significant changes in desipramine and 2-hydroxy-desipramine kinetics were observed during ketoconazole treatment.

Conclusions These findings indicate that ketoconazole, a relatively specific inhibitor of CYP3A4, inhibits the N-demethylation of imipramine without affecting the 2-hydroxylation of imipramine and desipramine. This interaction, confirms that CYP3A4 plays a role in the demethylation of tricyclic antidepressants.