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.

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

PERUCCA, EMILIO
1997-01-01

Abstract

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.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11571/472823
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact