ADMET-Absorption, Distribution, Metabolism, Excretion, and Toxicity

StatusFDA approved
AdministrationIM, IV
PharmacologyAn antidepressant medication, a tricyclic antidepressant of the dibenzazepine group. Imipramine is mainly used in the treatment of major depression and enuresis (inability to control urination).

Absorption_value98.0
Absorption (description)Readily absorbed after oral administration and widely distributed throughout the tissues.
Caco_2-4.85
Bioavailability42.0

MetabollsmImipramine undergoes considerable first-pass metabolism, mainly by demethylation to the primary active metabolite desipramine. Other major metabolic reactions include hydroxylation at the 2- or 10-positions followed by conjugation. Both pathways are genetically determined. 2-Hydroxyimipramine and 2-hydroxydesipramine appear to be active. Undergoes N-demethylation to desipramine, catalyzed by CYP2C19 (polymorphic), CYP1A2, and others; 2-hydroxylation is catalyzed by CYP2D6 (polymorphic).
Half lifeimipramine 16 h, increased in children, elderly subjects, and after overdose; desipramine 10 to 35 h.

ExcretionA large number of metabolites have been identified in the urine and less than 10% of a dose is excreted unchanged. A total of about 40% of a dose is excreted in the urine in 24 h and about 70% in 72 h. Of the urinary material, up to 40% consists of free and conjugated 2-hydroxydesipramine, up to about 25% is free and conjugated 2-hydroxyimipramine, and about 15% is free and conjugated 2-hydroxyiminodibenzyl; small amounts of didesmethylimipramine, free iminodibenzyl, and 10-hydroxydesipramine are also found. The excretion of unchanged drug and unconjugated metabolites is pH-dependent and is increased in acid urine. About 20% of a dose is eliminated in the faeces. Imipramine and desipramine cross the blood–brain barrier and placenta. They are excreted in breast milk in concentrations similar to those found in plasma.
Urinary Excretion<2
Clerance13 ml/min/kg, decreased in elderly subjects.

ToxicityIn adults the estimated minimum lethal dose is 1 g, although fatalities have occurred with less and patients have survived the ingestion of as much as 5 g. In children, as little as 350 mg may be fatal. Blood concentrations greater than 0.5 mg/L (imipramine and desipramine) may cause toxic effects and imipramine concentrations of 0.8 to 4.5 to 13 mg/L have been associated with fatalities.
LD50 (rat)N/A
LD50 (mouse)N/A