Influence of Quinidine on the Pharmacokinetics of Trimipramine and on Its Effect on the Waking EEG of Healthy Volunteers

Abstract

The pharmacokinetics and pharmacodynamics (waking EEG) of 75 mg trimipramine taken orally were determined in two healthy volunteers on two separate occasions, once without and once after comedication with 2 × 50 mg quinidine. Quinidine, a potent cytochrome P-450IID6 inhibitor, is used as a pharmacological tool to mimic a lack of this enzyme in man. In this study, it markedly altered the pharmacokinetics of trimipramine, almost doubling its plasma half-life and decreasing its apparent clearance and volume of distribution. These results strongly suggest that trimipramine is a substrate of cytochrome P-450IID6. These modifications of trimipramine metabolism were accompanied by measurable changes in some EEG variables, most notably with regard to the relative power in the alpha and theta bands, which showed higher and longer-lasting effects of trimipramine. Since cytochrome P-450IID6 is deficient in 5-10% of Caucasian subjects, this may have consequences in trimipramine-treated subjects, especially with regard to the effects of the drug on the EEG.

CYP2D6 and CYP2C19 genotype‐based dose recommendations for antidepressants: a first step towards subpopulation‐specific dosages

“…In‐vitro studies have implicated involvement of CYP2D6 in the hydroxylation of TRI (182). Co‐administration of quinidine, a potent inhibitor of CYP2D6, thus inhibited the formation of 2‐hydroxy‐TRI (100).…”

Effects of Polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on Trimipramine Pharmacokinetics

“…21 This is confirmed by interaction studies with the CYP2D6 inhibitors quinidine and paroxetine showing an increase of plasma trimipramine concentrations whereas formation of the 2-hydroxy metabolite was decreased. 22,23 Earlier studies suggested that N-demethylation of other tricyclic antidepressants (amitriptyline, 24 imipramine 25 ) is mediated by CYP2C19, the S-mephenytoin hydroxylase, and by CYP3A4. 26 Interaction studies with the CYP inhibitor fluvoxamine confirm involvement of CYP2C19 in trimipramine demethylation 27 but CYP1A2 might be involved as well, since fluvoxamine is a potent inhibitor of CYP1A2, too.…”

“…21 This is confirmed by interaction studies with the CYP2D6 inhibitors quinidine and paroxetine showing an increase of plasma trimipramine concentrations whereas formation of the 2-hydroxy metabolite was decreased. 22,23 …”

Trimipramine and Maprotiline Plasma Levels during Combined Treatment with Moclobemide in Therapy-Resistant Depression

“…It has been shown that 2-hydroxylation. but not N-demethylation of trimipramine is mediated by CYP 2D6 (Eap et al, 1992: Bofaji, 1993. Although there are some studies investigating the correlations between plasma concentration, and clinical response during treatment with maprotiline, no concrete studies have been published on the question of pharmacokinetic interactions in combination treatment with maprotiline apart from a combination with fluvoxamine (for review, see Goodnick, 1994).…”