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Author: Admin | 2025-04-28
2-4 weeks; the sedative action is not delayed. 5.2 Pharmacokinetic properties Absorption Film-coated tablets Amitriptyline 10 mg film-coated tablets, Amitriptyline 25 mg film-coated tablets Oral administration of tablets results in maximum serum levels in about 4 hours. (tmax= 3.89±1.87 hours; range 1.93-7.98 hours). After peroral administration of 50 mg the mean Cmax = 30.95±9.61 ng/ml; range 10.85-45.70 ng/ml (111.57±34.64 nmol/l; range 39.06-164.52 nmol/l). The mean absolute oral bioavailability is 53% (Fabc = 0.527±0.123; range 0.219-0.756). Amitriptyline 50 mg film-coated tablets After oral administration amitriptyline is absorbed slowly but completely. Due to the often delayed gastrointestinal tract passage maximum plasma concentrations are reached after 1 to 5 (-8) hours. The systemic bioavailability is about 50% of the intravenous injection. Distribution The apparent volume of distribution (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg). The plasma protein binding is about 95%. Amitriptyline and the main metabolite nortriptyline pass across the placental barrier. In nursing mothers amitriptyline and nortriptyline are excreted in small amounts with the breast milk. The ratio milk concentration/plasma concentration in women is around 1:1. The estimated daily infant exposure (amitriptyline + nortriptyline) averages 2% of the corresponding maternal weight related doses of amitriptyline (in mg/kg) (see section 4.6). Biotransformation In vitro the metabolism of amitriptyline proceeds mainly by demethylation (CYP2C19, CYP3A4) and hydroxylation (CYP2D6) followed by conjugation with glucuronic acid. Other isozymes involved are CYP1A2 and CYP2C9. The metabolism is subject to genetic polymorphism. The main active metabolite is the secondary amine, nortriptyline. Nortriptyline is a more potent inhibitor of noradrenaline than of serotonin uptake, while amitriptyline inhibits the uptake of noradrenaline and serotonin equally well. Other metabolites such as cis- and trans-10-hydroxyamitriptyline and cis- and trans-10-hydroxynortriptyline have the same profile as nortriptyline but is considerably weaker. Demethylnortriptyline and amitriptyline N oxide are only present in plasma in minute amounts; the latter is almost inactive. All the metabolites are less anticholinergic than amitriptyline and nortriptyline. In plasma the amount of total 10- hydroxynortriptyline dominates but most of the metabolites are conjugated. Elimination The elimination half-life (t½β) amitriptyline after peroral administration is about 25 hours (24.65±6.31 hours; range 16.49-40.36 hours). The mean systemic clearance (Cls) is 39.24±10.18 L/h, range 24.53- 53.73 L/h. The excretion proceeds mainly with urine. The renal elimination of unchanged amitriptyline is insignificant (about 2%). Steady state plasma levels of amitriptyline + nortriptyline are reached within a week for most patients, and in steady state the plasma level comprises approximately equal parts of amitriptyline and nortriptyline around the clock following treatment with conventional tablets 3 times a day. Elderly Longer half-lives and decreased oral (Clo) clearance values due to a reduced rate of metabolism have been demonstrated in elderly patients. Hepatic
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