Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: Macleods Pharmaceuticals SA (Pty) Ltd, Office Block 1, Bassonia Estate Office Park (East), 1 Cussonia Drive, Bassonia Rock, Ext. 12, Alberton, South Africa
A 1.2 Psychoanaleptics (antidepressants)
Escitalopram is a selective inhibitor of serotonin (5-HT)-uptake.
Escitalopram has minimal effect on noradrenaline (NA), dopamine (DA) and gamma aminobutyric acid (GABA) uptake. Escitalopram has no or very low affinity for a series of receptors including 5-HT1A, 5-HT2, DA D1 and D2 receptors, α1, α2, β-adrenoceptors, histamine H1, muscarinic, benzodiazepine and opioid receptors.
Absorption is independent of food intake (mean tmax is 4 hours after multiple dosing).
The apparent volume of distribution (Vd,β/F) after administration is about 12 to 26l/kg. The plasma protein binding of escitalopram is approximately 55%.
Escitalopram is metabolised in the liver to the demethylated and didemethylated metabolites. Alternatively, the nitrogen may be oxidised to form a N-oxide metabolite. Both parent compound and metabolites are partly excreted as glucuronides. Unchanged escitalopram is the predominant compound in plasma.
After multiple dosing the mean concentrations of the demethyl and didemethyl metabolites are usually 28-31% and <5% of the escitalopram concentration, respectively. Biotransformation of escitalopram to the demethylated metabolite is mediated by a combination of CYP2C19, CYP3A4 and CYP2D6.
The elimination half-life after multiple dosing is about 30 hours and the plasma clearance after oral administration (Cloral) is about 0,6 l/min. Escitalopram and major metabolites are assumed to be eliminated both by the hepatic (metabolic) and the renal routes, with the major part of the dose excreted as metabolites in urine.
Hepatic clearance is mainly by the P450 enzyme system. CYP2C19 is the primary isoenzyme involved in the demethylation of escitalopram, followed by CYP3A4 and CYP2D6. There is linear pharmacokinetics. Steady-state plasma levels are achieved in about 1 week. Average steady-state concentrations of 50 nmol/l (range 20 to 125 nmol/l) are achieved at a daily dose of 10 mg.
A longer half-life (about 50%) and decreased clearance values, due to a reduced rate of metabolism, have been demonstrated in the elderly.
Escitalopram is eliminated more slowly in patients with reduced hepatic function. The half-life of escitalopram is twice as long in patients with hepatic impairment and steady state escitalopram concentrations at a given dose will be approximately twice as high as in patients with normal liver function.
Escitalopram is eliminated more slowly in patients with mild to moderate reduction of renal function with no major impact on the escitalopram concentrations in serum. At present no information is available for the treatment of patients with severely reduced renal function (creatinine clearance <30 ml/min).
Based on in vitro results with escitalopram, genetic polymorphism with respect to CYP2D6 is not known; with respect to CYP2C19, it may be of clinical relevance, as shown in a limited number of patients.
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