Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants, and by quinidine and ketoconazole: a model system to predict drug interactions in vivo.

Biotransformation of the tricyclic antidepressant desipramine (DMI) to its metabolite 2-hydroxy-desipramine (2-OH-DMI) was studied in vitro using microsomal preparations from human, monkey, mouse and rat liver. In all species 2-OH-DMI was the principal identified metabolite. Mean (+/- S.E.) reaction parameters in six human liver samples were: Vmax, 0.11 +/- .02 nmol/ml/min/mg protein; Km, 16.1 +/- 4.2 microM. Quinidine was a highly potent inhibitor of 2-OH-DMI formation (mean Ki = 0.053 microM), consistent with the presumed role of Cytochrome P450-2D6 in mediating this reaction. Ketoconazole was a much less potent inhibitor (mean Ki = 10.3 microM). Two serotonin-specific reuptake inhibitor (SSRI) antidepressants, and their respective metabolites, were evaluated as potential inhibitors of 2-OH-DMI formation. Fluoxetine (FLU) and norfluoxetine (NOR) were the most potent inhibitors (mean Ki values: 3.0 and 3.5 microM, respectively). Sertraline (SERT) and its metabolite desmethylsertraline (DES) also inhibited the reaction (mean Ki: 22.7 and 16.0 microM), but were significantly less potent than FLU or NOR. Values of Ki and Km measured in vitro were used to generate a theoretical prediction of the degree of clearance inhibition in vivo at any given concentration of substrate and inhibitor. The model was applied to a clinical study in which DMI clearance in humans was impaired by coadministration of FLU (yielding FLU and NOR in plasma) or by SERT (yielding SERT and DES in plasma). Use of plasma SSRI concentrations in the predictive model underestimated the actual impairment of DMI clearance.(ABSTRACT TRUNCATED AT 250 WORDS)