Tricyclic antidepressants + Macrolides - Drug Interactions

Troleandomycin increases plasma levels of imipramine, andan isolated report suggests that josamycin may possibly increaseamitriptyline serum levels. Erythromycin may possibly raise clomipramine levels,but was not found to interact with other tricyclic antidepressants in one study.

Clinical evidence,mechanism, importance and management

Erythromycin 250mg four times daily for 6 days was found not to affect tricyclic antidepressant levels of 8 patients taking desipramine, imipramine, doxepin, or nortriptyline (See reference number 1). Behavioural changes have been reported in a 15-year-old patient when erythromycin was added to a regimen of clomipramine and risperidone,(See reference number 2) resulting in symptoms compatible with serotonin syndrome, although mental confusion and autonomic instability were absent (See reference number 3). It was suggested that erythromycin increased clomipramine levels by inhibiting its metabolism by cytochrome P450 isoenzyme CYP3A4 (See reference number 4). Clomipramine levels may also have been raised by competition with risperidone for metabolism by CYP2D6.

A patient taking amitriptyline had a marked increase in total serum levels of amitriptyline and its metabolite, nortriptyline, after taking josamycin but no toxicity was reported. It was suggested that josamycin had inhibited amitriptyline metabolism (See reference number 5). This is only an isolated case and its general significance is unknown.

A study in 9 healthy Chinese men found that when they were given troleandomycin 250mg daily for 2 days before a single 100mg oral dose of imipramine, AUC of imipramine was increased by 59 % and its oral clearance was reduced by 30%. It is thought that troleandomycin inhibits N-demethylation of imipramine by inhibiting cytochrome P450 isoenzyme subfamily CYP3A (See reference number 6). The clinical importance of this interaction is uncertain,but it may be prudent to be alert for increased antimuscarinic adverse effects (e.g. dry mouth,blurred vision, urinary retention).

Amsterdam JD,Maislin G. Effect of erythromycin on tricyclic antidepressant metabolism. J Clin Psychopharmacol (1991) 11, 203–6.

Fisman S,Reniers D, Diaz P. Erythromycin interaction with risperidone or clomipramine in anadolescent. J Child Adolesc Psychopharmacol (1996) 6, 133–8.

Fisman S,Diaz P. Erythromycin and clomipramine: Noncompetitive inhibition of demethylation. Reply. J Child Adolesc Psychopharmacol (1996) 6, 213.

Oesterheld JR. Erythromycin and clomipramine: Noncompetitive inhibition of demethylation.J Child Adolesc Psychopharmacol (1996) 6,211–12.

Sánchez Romero A,Calzado Solaz C. Posible interacción entre josamicina y amitriptilina. Med Clin (Barc) (1992) 98, 279.

Wang J-S,Wang W, Xie H-G, Huang S-L, Zhou H-H. Effect of troleandomycin on the pharmacokinetics of imipramine in Chinese: the role of CYP3A. Br J Clin Pharmacol (1997) 44, 195–8.