The primary use of tricyclic antidepressants (TCAs) for treatment of depression has decreased with the introduction of the selective serotonin reuptake inhibitors (SSRIs) [Article:10319193]. The SSRIs have a more tolerable adverse-effect profile and decreased risk for toxicity [Article:16553509]. But the TCAs remain an effective therapeutic option for certain types of depressive illnesses, such as major depression with melancholic features and post-stroke depression [Articles:8835647, 12893112]. The TCAs also have been recognized as beneficial treatment for fibromyalgia, neuropathic pain, and migraine prophylaxis [Articles:11029681, 12230591, 15336464]. Desipramine appears to be effective in the treatment of adult attention-deficit/hyperactivity disorder [Article:16732717].
After oral administration, TCAs are rapidly absorbed. TCAs are lipophilic compounds and therefore exhibit a large volume of distribution. They bind to plasma albumin and also to extravascular tissues [Article:10319193]. TCAs reach a peak plasma concentration within 2-6 hours. They are subjected to extensive hepatic metabolism by P450 isoenzymes and less than 5% of a TCA dose is eliminated unchanged [Article:10319193].
CYP2C19 activity is associated with the N-demethylation of tertiary amine TCA. P450 isoenzymes CYP1A2 and CYP3A4 also participate in tricyclic demethylation [Articles:10319902, 9084901, 17471183]. The tertiary amine imipramine is typically metabolized by demethylation to the secondary active metabolite desipramine. Desipramine is also a tricyclic drug by itself. Both tertiary and secondary amines are metabolized, mainly through hydroxylation by CYP2D6, to 2-OH- imipramine and 2-OH-desipramine [Articles:10319193, 16553509]. Hydoxy-metabolites of TCAs have similar or shorter half-lives and smaller distribution volumes than their parent compounds [Articles:7461025, 2687861]. Glucuronide conjugation of TCA hydroxylated metabolites improves their water solubility and therefore promotes more efficient renal excretion. However, hydroxy metabolites are also cleared into urine in their unconjugated form [Article:2116227]. Commonly, the clearance of TCAs is observed to be proportional to the drug concentration, but some studies showed a saturation of the P450 hydroxylation with dose-dependent kinetics at high doses of imipramine and desipramine [Articles:1813901, 10319193, 3709631, 6467794, 2687860].
The dose range of many tricyclic antidepressants is between 25 - 300 mg/day. Genetically-based differences in the activity of CYP2C19 and CYP2D6 account in large part for the wide interindividual variability in the drugs metabolism and plasma concentration [Article:10319193]. Depending on the antidepressant, CYP2C19 poor metabolizers, as well as CYP2D6 poor metabolizers, may generate plasma drug levels several fold higher during routine dosing [Articles:15037866, 16384813]. Toxic effects, like agitation, confusion, and pacing, are seen in patients with TCA plasma concentrations greater than 450-500ng/ml [Article:9139291]. Major toxicity and death is associated with concentrations above 1000ng/ml [Articles:17471183, 9139291]. In terms of drug interactions, desipramine is not a strong inhibitor of CYP2D6, but imipramine significantly inhibits CYP2C19 and CYP1A2 [Article:17471183].
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
If you would like to reproduce this PharmGKB pathway diagram, please acknowledge the copyright to PharmGKB and state that permission has been given by PharmGKB and Stanford University. Also, please send a brief email to firstname.lastname@example.org to inform us of which pathway diagram you are using and for what purpose.
Entities in the Pathway
Drugs/Drug Classes (2)
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|2-Hydroxydesipramine||2-Hydroxydesipramine glucuronide||10319193, 16553509, 1813901, 2687860, 2687861, 3709631, 6467794, 7461025|
|2-Hydroxyimipramine||2-Hydroxyimipramine glucuronide||10319193, 16553509, 1813901, 2687860, 2687861, 3709631, 6467794, 7461025|
|desipramine||2-Hydroxydesipramine||CYP2D6||10319193, 16553509, 1813901, 2687860, 2687861, 3709631, 6467794, 7461025|
|imipramine||2-Hydroxyimipramine||CYP2D6||10319193, 16553509, 1813901, 2687860, 2687861, 3709631, 6467794, 7461025|
|imipramine||desipramine||CYP1A2, CYP2C19, CYP3A4||10319902, 9084901|
Download data in TSV format. Other formats are available on the Downloads/LinkOuts tab.