Laroxyl

Absorption

Oral administration of tablets results in maximum serum levels in about 4 hours. (t_max = 3.89±1.87 hours; range 1.93-7.98 hours). After peroral administration of 50 mg the mean C_max = 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% (F_abs = 0.527±0.123; range 0.219-0.756).

Distribution

The apparent volume of distribution (V_d)_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%.

Laroxyl and the main metabolite nortriptyline pass across the placental barrier.

In nursing mothers Laroxyl 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 (Laroxyl + nortriptyline) averages 2% of the corresponding maternal weight related doses of Laroxyl (in mg/kg).

Biotransformation

In vitro the metabolism of Laroxyl 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 Laroxyl inhibits the uptake of noradrenaline and serotonin equally well. Other metabolites such as cis- and trans-10-hydroxyLaroxyl and cis- and trans-10-hydroxynortriptyline have the same profile as nortriptyline but is considerably weaker. Demethylnortriptyline and Laroxyl N oxide are only present in plasma in minute amounts; the latter is almost inactive. All the metabolites are less anticholinergic than Laroxyl and nortriptyline. In plasma the amount of total 10-hydroxynortriptyline dominates but most of the metabolites are conjugated.

Elimination

The elimination half-life (t_½ β) Laroxyl after peroral administration is about 25 hours (24.65±6.31 hours; range 16.49-40.36 hours). The mean systemic clearance (Cl_s) 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 Laroxyl is insignificant (about 2%).

Steady state plasma levels of Laroxyl + nortriptyline are reached within a week for most patients, and in steady state the plasma level comprises approximately equal parts of Laroxyl and nortriptyline around the clock following treatment with conventional tablets 3 times a day.

Elderly patients

Longer half-lives and decreased oral (Cl_o) clearance values due to a reduced rate of metabolism have been demonstrated in elderly patients.

Reduced hepatic function

Hepatic impairment may reduce hepatic extraction resulting in higher plasma levels and caution should be exercised when dosing these patients.

Reduced renal function

Renal failure has no influence on the kinetics.

Polymorphism

The metabolism is subject to genetic polymorphism (CYP2D6 and CYP2C19).

Pharmacokinetic/pharmacodynamic relationship

Plasma concentrations of Laroxyl and nortriptyline vary very widely between individuals and no simple correlation with therapeutic response has been established.

The therapeutic plasma concentration in major depression is around 80 - 200 ng/ml (≈ 280 - 700 nmol/l) (for Laroxyl + nortriptyline). Levels above 300-400 ng/ml are associated with increased risk of disturbance in cardiac conduction in terms of prolonged QRS-complex or AV block.

Absorption

Oral administration of tablets results in maximum serum levels in about 4 hours. (t_max= 3.89±1.87 hours; range 1.93-7.98 hours). After peroral administration of 50 mg the mean C_max = 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% (F_abs = 0.527±0.123; range 0.219-0.756).

Distribution

The apparent volume of distribution (V_d)_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).

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 (t_1/2β) amitriptyline after peroral administration is about 25 hours (24.65±6.31 hours; range 16.49-40.36 hours). The mean systemic clearance (Cl_s) 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 patients

Longer half-lives and decreased oral (Cl_o) clearance values due to a reduced rate of metabolism have been demonstrated in elderly patients.

Reduced hepatic function

Hepatic impairment may reduce hepatic extraction resulting in higher plasma levels and caution should be exercised when dosing these patients.

Reduced renal function

Renal failure has no influence on the kinetics.

Polymorphism

The metabolism is subject to genetic polymorphism (CYP2D6 and CYP2C19).

Pharmacokinetic/pharmacodynamic relationship

Plasma concentrations of amitriptyline and nortriptyline vary very widely between individuals and no simple correlation with therapeutic response has been established.

The therapeutic plasma concentration in major depression is around 80 - 200 ng/ml (≈ 280 - 700 nmol/l) (for amitriptyline + nortriptyline). Levels above 300-400 ng/ml are associated with increased risk of disturbance in cardiac conduction in terms of prolonged QRS-complex or AV block.

Nenhum conhecido

Na ausência de estudos de compatibilidade, este medicamento não deve ser misturado com outros medicamentos.

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