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PubMed · 12398564

Pharmacokinetic interaction between nortriptyline and terbinafine.

P-Hugo M Van Der Kuy·Harrie A Van Den Heuvel·Rob W Kempen·Leo M L Vanmolkot
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Abstract

OBJECTIVE: To clarify the mechanism of interaction between nortriptyline and terbinafine. CASE SUMMARY: Nortriptyline intoxication secondary to terbinafine treatment was observed in a woman with a major depressive disorder. This is the second report of this interaction. A rechallenge was performed during which serum concentrations were measured of nortriptyline and the 2 hydroxy metabolites. To document the case, genotyping of CYP2D6 was also performed. DISCUSSION: Metabolism by CYP2D6 is of major importance for the hydroxylation of nortriptyline, making it susceptible to competitive inhibition by terbinafine. CONCLUSIONS: The pharmacokinetic interaction between nortriptyline and terbinafine is probably due to inhibition of CYP2D6 of the nortriptyline metabolism by terbinafine. The interaction is not restricted to a subpopulation, but may occur even in persons without deviations in CYP2D6.

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Antidepressive Agents, TricyclicCytochrome P-450 CYP2D6Cytochrome P-450 CYP2D6 InhibitorsDepressive DisorderDrug InteractionsEnzyme InhibitorsFemaleHumansMiddle AgedNaphthalenesNortriptylineTerbinafineCase ReportsJournal Article

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P-Hugo M Van Der Kuy, Harrie A Van Den Heuvel, Rob W Kempen, Leo M L Vanmolkot. 2002. Pharmacokinetic interaction between nortriptyline and terbinafine.. https://doi.org/10.1345/aph.1c083

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PubMed2006

Inhibition of astroglial inwardly rectifying Kir4.1 channels by a tricyclic antidepressant, nortriptyline.

The inwardly rectifying K(+) (Kir) channel Kir4.1 is responsible for astroglial K(+) buffering. We examined the effects of nortriptyline, a tricyclic antidepressant (TCA), on Kir4.1 channel currents heterologously expressed in HEK293T cells, using a whole-cell patch-clamp technique. Nortriptyline (3-300 microM) reversibly inhibited Kir4.1 currents in a concentration-dependent manner, whereas it marginally affected neuronal Kir2.1 currents. The inhibition of Kir4.1 channels by nortriptyline depended on the voltage difference from the K(+) equilibrium potential (E(K)), with greater potency at more positive potentials. Blocking kinetics of the drug could be described by first-order kinetics, where dissociation of the drug slowed down and association accelerated as the membrane was depolarized. The dissociation constant (K(d)) of nortriptyline for Kir4.1 inhibition was 28.1 microM at E(K). Other TCAs, such as amitriptyline, desipramine, and imipramine, also inhibited Kir4.1 currents in a similar voltage-dependent fashion. This study shows for the first time that nortriptyline and related TCAs cause a concentration-, voltage-, and time-dependent inhibition of astroglial K(+)-buffering Kir4.1 channels, which might be involved in therapeutic and/or adverse actions of the drugs.

Antidepressive Agents, Tricyclic↗