Imipramine metabolites in blood of patients during therapy and after overdose.

Plasma or serum concentrations of imipramine and five of its nonconjugated metabolites (desipramine, 2-OH-imipramine, 2-OH-desipramine, imipramine-N-oxide, and didesipramine) were followed in three cases of imipramine overdose and during steady state in 24 patients on continuous imipramine treatment. In the overdose cases the imipramine and desipramine concentrations declined monoexponentially with t 1/2s of 12 to 21 and 31 to 37 hr. The 2-OH-imipramine and 2-OH-desipramine levels were lower and declined in parallel with their corresponding parent compounds. In the patients on continuous imipramine treatment, the steady-state levels of 2-OH-imipramine and 2-OH-desipramine were very low or immeasurable (less than 15 nmol/l) in five patients. In most patients (n = 18) the hydroxymetabolite levels were much higher with 2-OH-imipramine/imipramine ratios of 0.09 to 0.45 and 2-OH-desipramine/desipramine ratios of 0.36 to 0.86. In one patient there were particularly high ratios (2-OH-imipramine/imipramine, 0.85; 2-OH-desipramine/desipramine, 1.30). The patients with very low hydroxymetabolite levels had considerably higher desipramine levels than the others, indicating that the low metabolite levels were due to poor hydroxylation. In one of these poor hydroxylators a desipramine t 1/2 of about 120 hr was estimated after imipramine discontinuation. With increased imipramine dose the 2-OH-imipramine levels tended to rise little or not at all. Imipramine-N-oxide could only be detected in the overdose cases during the first 6 to 12 hr and didesipramine was generally present only when the desipramine levels were above 200 nmol/l.