Comparison of the metabolism of the three antidepressants amitriptyline, imipramine, and chlorimipramine in vitro in rat liver microsomes

Abstract

The metabolism of the tricyclic antidepressants amitriptyline (AMI), imipramine (IMI), chlorimipramine (CMI) and some of their metabolites was studied in vitro in isolated liver microsomes of female Spraque-Dawley rats. Nine metabolites of AMI, seven metabolites of IMI, and 11 metabolites of CMI were quantitatively determined with high-performance liquid chromatography. The main metabolic reactions, mediated by an NADPH generating system, were hydroxylation, demethylation, and N-oxidation. The ratio of these reactions was different for the three drugs. AMI was hydroxylated more than CMI and CMI more than IMI. The order for demethylation was CMI greater than AMI = IMI, the order for N-oxidation IMI greater than CMI less than or equal to AMI. The substrate dependence of metabolism was investigated. Demethylation and N-oxidation increased proportionally to increasing substrate concentrations, whereas formation of hydroxylated metabolites became saturated (in the concentration range of 10(-6)-10(-5) M). The in vitro metabolism was compared with the in vivo metabolism in humans, reflected by the plasma concentrations of these drugs and their metabolites. A good agreement in metabolic pathways was found.

Plasma and brain pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites after acute intraperitoneal injection in mice

“…Estimating the extent of metabolism in terms of AUC values, hydroxylation appears to be overall a more important pathway than demethylation, and 1O-0H-NOR is the main plasma metabolite, with its E-and Z-isomers in the same proportions. Hydroxylation of NOR seems to be the main metabolic reaction, as previously described by Kruger et al (25), in so far as 1O-0H-NOR levels correlate better with NOR-levels than with 1O-0H-AMI levels (r = 0.64 and 0.20, respectively). However, demethylation of 1O-0H-AMI may also initially contribute to 1O-0H-NOR formation; 1O-0H-AMI plasma levels are, during the first hour, as high as NOR levels but then decrease rapidly, perhaps because of saturation of hydroxylation of AMI by high levels of parent compound AMI.…”

“…However, demethylation of 1O-0H-AMI may also initially contribute to 1O-0H-NOR formation; 1O-0H-AMI plasma levels are, during the first hour, as high as NOR levels but then decrease rapidly, perhaps because of saturation of hydroxylation of AMI by high levels of parent compound AMI. Such saturation has previously been suggested in in vitro studies by Kruger et al (25). On the contrary, the weaker but more prolonged NOR levels do not induce NOR-hydroxylation saturation.…”

Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients

“…A similar effect has also been shown for fluoxetine (Vaughan 1988;Rosenstein et al 1991;Vandel et al 1991). While much is known about quasi-irreversible methylations which mostly use S-adenosyl-L-methionine as methyl donor (for review see Chawla et al 1990), only few investigations dealt with demethylations (Henderson and Mazel 1964;Clarke and O'Connor 1983;Krfiger et al 1986). Since there were no obvious differences between the four antidepressants tested for interference, it seemed likely that a common enzyme is responsible for N-demethylation of different antidepressants.…”

Comparative oxidative metabolic profiles of clomipramine in cats, rats and dogs: preliminary results from an in vitro study

“…Clomipramine is a lipophilic compound that is mainly eliminated by oxidation catalyzed by the cytochrome P450 enzyme system in the liver in humans (Nielsen et al. , 1996) and in rats (Kruger et al. , 1986).…”

“…, 1986). The main route is N ‐demethylation to the active metabolite, desmethylclomipramine (DCMP) catalyzed by CYP3A4, CYP2C19, CYP2C9 and CYP1A2 (Kruger et al. , 1986; Nielsen et al.…”