Active metabolites of imipramine and desipramine in man

Abstract

Active hydroxy metabolites of imipramine (IMI) and desipramine (DMI) have been quantified in plasma and cerebrospinal fluid (CSF) from patients at steady-state. In plasma of prepubescent boys and adults the concentration of unconjugated 2-hydroxyimipramine is only 15% to 25% that of IMI; 2-hydroxydesipramine (OH-DMI) concentration, however, is usually 50% that of DMI and in some cases OH-DMI is the predominant compound. In CSF from adult patients the ratio of concentrations of OH-DMI/DMI is higher than in plasma. Judging from the CSF/plasma ratio 12% of DMI exists in the free form at steady state, whereas 16% of OH-DMI is free (P less than 0.02). There is no evidence for saturation of hydroxylation within the therapeutic dose and concentration ranges investigated. On the basis of a steady-state OH-DMI/DMI ratio of less than 1/30 in plasma 5% of the population studied could be classified as deficient DMI hydroxylators. This in the same as the incidence of deficient debrisoquine hydroxylators reported in other populations.

The Use of In Vitro Data and Physiologically-Based Pharmacokinetic Modeling to Predict Drug Metabolite Exposure: Desipramine Exposure in Cytochrome P4502D6 Extensive and Poor Metabolizers Following Administration of Imipramine

“…2), N-demethylation is the major pathway with the highest fraction of total clearance of the parent drug (f CL,m = 0.44-0.62). Potter et al (1982) demonstrated a similar finding that desipramine was the major circulating metabolite quantified in patient plasma (accounted for 67% total concentration of metabolites). By measuring the AUCs of desipramine in the PK studies whether desipramine was given as parent compound or formed from imipramine, Brosen et al (1986) calculated the demethylation fraction of imipramine after the i.v.…”

Age differences in the sensitivity to clomipramine in an animal model of obsessive-compulsive disorder

“…Pharmacokinetic clinical studies have shown a lower tissue concentration, faster hepatic metabolism and lower availability of CMI in young subjects compared to adults. Indeed, the shorter elimination half-life in prepubertal subjects has been suggested as a reason for the delay to reach a therapeutic effect (Potter et al 1982). In the present study, a pharmacokinetic factor does not entirely explain the lack of action of CMI since even the dose of 15 mg/kg or prolonged treatment for 5 consecutive days, had no action in young rats while in adults, both doses, 10 and 15 mg/ kg, effectively prevented the actions of 8-OH-DPAT.…”

Tricyclic antidepressants block N‐methyl‐D‐aspartate receptors: similarities to the action of zinc

“…In clinical studies of antidepressant actions, '4 _3 cerebrospinal fluid (CSF) concentrations of 100-150 ng ml-have been measured following routine therapy (Potter et al, 1982 , the physiological function of the Zn2+ binding site in situ is entirely unknown. Thus, it is not clear whether Zn2+ tonically occupies such binding sites, or whether it is released in response to some modulatory input at NMDA synapses.…”