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

E. Spina, A. Avenoso, G. M. Campo, M. G. Scordo, A. P. Caputi, E. Perucca

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)315-318
Number of pages4
JournalBritish Journal of Clinical Pharmacology
Issue number3
Publication statusPublished - 1997


  • CYP2D6
  • CYP3A4
  • desipramine
  • drug interaction
  • imipramine
  • ketoconazole

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)


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