Tricyclic antidepressant and metabolite levels in chronic renal failure

Abstract

Serial blood samples were drawn from 12 patients undergoing hemodialysis who were receiving tricyclic antidepressants (TCAs). Samples were drawn before, during, and after a dialysis session (2-17 sessions per subject). Samples were analyzed by HPLC [high performance liquid chromatography] before and after hydrolysis with .beta.-glucuronidase/sulfatase to determine the conjugated and nonconjugated metabolites. Analyis of these data in comparison with those of controls with depression and normal renal function showed that: at steady state, tertiary and secondary amine TCA levels did not differ; levels of the hydroxylated metabolites had greater variability and were somewhat higher at steady state; levels of the conjugated hydroxylated compounds were markedly elevated, reaching 500-1500% normal; the time to reach a steady-state level appeared to be slightly increased; and elimination half-times of unconjugated and conjugated drug forms were longer in patients with normal renal function than those reported in the literature. Levels of the tertiary, secondary and hydroxylated metabolites were not changed by dialysis, whereas there were substantial decrements in glucuronidated metabolite levels. These findings demonstrate increased concentrations of conjugated drug forms and suggest an abnormal distribution or delayed elimination of unconjugated and conjugated metabolites. These observations may shed some light on the apparent hypersensitivity of these patients to TCA side effects, particularly because glucuronides may exert peripheral pharmcologic effects.