title: Effect of ketoconazole on the pharmacokinetics of imipramine and desipramine in healthy subjects.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Pharmacology, University of Messina, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Spina
authors.forename: A
authors.initials: A
authors.lastname: Avenoso
authors.forename: G M
authors.initials: GM
authors.lastname: Campo
authors.forename: M G
authors.initials: MG
authors.lastname: Scordo
authors.forename: A P
authors.initials: AP
authors.lastname: Caputi
authors.forename: E
authors.initials: E
authors.lastname: Perucca
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003891:Desipramine / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006801:Humans; D007099:Imipramine / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D000935:Antifungal Agents; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007099:Imipramine; D007654:Ketoconazole; D003891:Desipramine