Page 24 - ITPS-6-2

INNOSC Theranostics and
Pharmacological Sciences TDM of imipramine: Correlation and case study

between 180 µg/L and 350 µg/L. leads to the accumulation of metabolites which can
2. Free fraction: The unbound or free fraction of lead to adverse drug reactions .
[13]
imipramine in the bloodstream should be <10%. 3. Patients with hepatic diseases: Hepatic impairment
3. Bioavailability: The bioavailability of imipramine is results in the implication of cytochrome P450
approximately 40%. isoenzyme. Alteration in clearance and plasma
4. Volume of distribution: The volume of distribution of concentration, reduction in the first-pass effect,
imipramine is about 20 L/kg. and prolongation of the elimination half-life can be
[14]
5. Clearance: The clearance of imipramine from the observed .
body is approximately 0.9 L/kg/h. 4. Patients with renal failure: Renal failure can result
6. Half-life: The half-life of imipramine is approximately in the accumulation of the metabolite desipramine
20 h. leading to toxicity .
[15]
5. Patients with cardiovascular diseases: A decrease in
Imipramine undergoes extensive hepatic metabolism cardiac output results in reduced hepatic blood flow
and its clearance is solely dependent on hepatic metabolism. with an increase in bioavailability .
[16]
Only 5% of the drug is excreted unchanged through
urine. The major metabolic pathways for imipramine are 5. Pharmacodynamics
demethylation and hydroxylation followed by glucuronide
conjugation, while the minor pathways include N-oxidation The pharmacodynamics of imipramine included:
and dealkylation. The metabolites of imipramine undergo 1. Dose-response relationship: The relationship between
further metabolism, including ring hydroxylation of the the concentration of imipramine and its response is
parent compound or N-demethylation of the side chain sigmoidal with a therapeutic threshold of 180 ng/mL.
[10]
before being excreted in urine or bile . Concentrations below 150 ng/mL show no response,
whereas concentrations above 450 ng/mL show
Imipramine is a highly lipophilic basic compound that toxicity. Higher doses lead to seizures and OCD, thus
is ionizable at stomach pH. Its rate of absorption is rapid requiring dose adjustment .
[17]
with maximum plasma concentration occurring 2 – 8 h 2. Concentration and toxicity: Mainly anticholinergic
after administration. The effect of food has no significant and cardiovascular side effects can be observed.
impact on the absorption of imipramine. However, the Delirium can be observed at concentrations of
first-pass effect decreases its bioavailability up to 20 – 70%, 450 ng/mL, seizures at 745 ng/mL, and overdose may
leading to decreased clearance and plasma concentration. lead to death .
[18]
Imipramine has an extraction ratio of up to 0.3 – 0.75,
and changes in hepatic blood flow can affect its clearance. 5.1. Factors affecting the dose–response relationship
Imipramine follows a non-linear kinetics . There are several factors affecting the relationship between
[11]
Imipramine has a large volume of distribution of up to the concentration and response of imipramine:
3 – 63 L/kg, and its highest concentration is found in the 1. Active metabolite: Hepatic metabolism produces
lung, kidney, brain, liver, and skeletal muscle. The lowest active metabolites which have longer half-lives.
concentration is found in plasma and adipose tissues. Monitoring of hydroxy metabolite may be necessary
Imipramine has a partition coefficient of 1000 – 100000 . to avoid toxicity [19,20] .
[11]
2. Protein binding: Imipramine binds to alpha-1 acid
4.2. Special populations glycoprotein, lipids, and cholesterol. The unbound
Certain populations require different imipramine doses fraction for imipramine is 4.2% to 10.9%. Methods for
due to the reasons listed as follows: TDM include ultrafiltration and equilibrium dialysis-
[20,21]
1. Pediatrics: Pediatrics patients have a higher proportion free drug concentration assays .
of lean body mass than fatty tissues, which leads to 3. Drug interactions: Drug interactions may occur on
altered tissue stores. Furthermore, due to the increase the levels of pharmacodynamic and pharmacokinetic.
in hepatic area, they show an increase in metabolism. Enzyme induction, increased hepatic clearance,
In neonates, a higher unbound fraction of imipramine cigarette smoking, inhibition of cytochrome P450
is observed at 26% which may lead to toxicity . isoenzymes, and use of antihistamines, selective
[12]
2. Geriatrics: Geriatric patients may show reduced serotonin reuptake inhibitors, other psychotropic
hepatic blood flow leading to a slower clearance, and drugs, and alcohol are some known factors that can
[22,23]
changes in the volume of distribution lead to low lead to drug interactions with imipramine .
clearance. They may also show a decreased half-life Imipramine is contraindicated in patients with a history
with no change in clearance. Decreased renal flow of hypersensitivity to TCAs, recent myocardial infarction,

Volume 6 Issue 2 (2023) 4 https://doi.org/10.36922/itps.0505