Persistent impairment of clomipramine demethylation in recently detoxified alcoholic patients.

The purpose of the present study was to investigate whether the metabolism of clomipramine is altered by chronic alcohol drinking. Eleven recently detoxified alcoholic patients were included (experimental group EG) and compared to a reference group of patients with no history of alcoholism (reference group RG, n = 102). Blood concentrations of clomipramine and its metabolites were measured as part of the routine drug monitoring program. Clearances were estimated from trough concentrations, according to a model developed previously. Results indicate strong inhibition of demethylation clearance in group EG, when compared to group RG (median values 9.9 and 24.2 L/h), with significant increase of the clomipramine to desmethylclomipramine ratio (median values 1.00 and 0.36). No difference was found for hydroxylation. In addition, high correlation is observed between hydroxylation and demethylation clearances in group EG (Spearman rs = 0.82), but not in reference group RG (rs = 0.29). Follow-up data indicate that impairment of demethylation capacity can persist for several weeks or months after withdrawal from alcohol. The interest of calculating clomipramine to desmethylclomipramine ratios during routine drug monitoring is emphasized, values of 1 or larger often being associated with liver disease and/or alcohol-related problems.