Steady-state plasma levels of clomipramine and its metabolites : impact of the sparteine/debrisoquine oxidation polymorphism

After an initial placebo week, 37 depressed inpatients were treated with the fixed dose of 75 mg clomipramine b.d. A sparteine test was carried out during the placebo period and again during the second week of active therapy. Clomipramine and four metabolites (desmethylclomipramine, didesmethylclomipramine, 8-hydroxyclomipramine, and 8-hydroxydesmethylclomipramine) in plasma were assayed by reversed HPLC. The clomipramine and desmethylclomipramine steady-state plasma levels varied by factors of 11 and 9, respectively, and the clomipramine/8-hydroxyclomiramine and desmethylclomipramine /8-hydroxydesmethylclomipramine ratios both varied by 7-fold. The results suggest that the 8-hydroxylation of clomipramine and of desmethylclomipramine are catalyzed by the same isozyme that oxidises sparteine, CYP2D6. The N-demethylation of clomipramine appears to be less clearly related to the activity of CYPD6. Clomipramine appeared to cause more potent inhibition of sparteine oxidation than that seen previously with other tricyclic antidepressants.