Source: Υπουργείο Υγείας (CY) Revision Year: 2016 Publisher: MUNDIPHARMA PHARMACEUTICALS LTD., 13, Othellos str., Dhali Industrial Zone, P.O. Box 23661, 1685 Nicosia, Cyprus Telephone number: +357 22815656 Fax Number: +357 22487833 E-mail: info@Mundipharma.com.cy ...
Pharmacotherapeutic group: Respiratory
ATC code: R05CB06
Ambroxol is an active N-desmethyl metabolite of bromhexine.
Ambroxol stimulates, by means of a direct attack on the gland cells, the production of a tracheobronchial secretion of lower viscosity.
In addition ambroxol affects bronchial secretion. By means of the increased formation of lysosomal enzymes, the mucous viscosity is reduced. A further expectorant promoting mechanism is based on the improved mucociliary transport resulting from the stimulation of ciliary motility.
In addition, an increase of the synthesis and secretion of surfactant (“surfactant activation”) following the administration of ambroxol has been reported and indications of an increase in the permeability of the bronchovascular barrier have also been detected.
The onset of action is observed, on average, 30 minutes after oral administration and the effect lasts for 6–12 hours, depending on the amount of the single dose.
Ambroxol is rapidly and almost completely absorbed after oral administration in humans.
Tmax after oral administration is 1–3 hours. Due to a first-pass metabolism, the absolute bioavailability after oral administration is reduced by about one-third. This also results in the formation of metabolites which pass through the kidney (e.g. dibromanthranilic acid, glucuronides). The binding to plasma protein is about 85% (80–90%). The terminal plasma half-life of the sum of ambroxol and its metabolites is about 22 hours.
Excretion is via the kidneys 90% in the form of the metabolites formed in the liver. Less than 10% of the substance excreted with the urine is in the form of unchanged ambroxol.
Because of the high level of binding to proteins, the high distribution volume and the slow redistribution from the tissue into the blood, no significant elimination of ambroxol through dialysis or forced diuresis is to be expected.
In severe liver disease the clearance of ambroxol is reduced by 20-40%. In several disorders of the renal function the elimination half-life of the metabolites of ambroxol is prolonged.
Ambroxol crosses the spinal-fluid barrier and the placental barrier and passes into the mother’s milk.
Ambroxol hydrochloride has a low index for acute toxicity. In repeat-dose studies, oral doses of 150 mg/kg/day (mouse, 4 weeks), 50 mg/kg/day (rat, 52 and 78 weeks), 40 mg/kg/day (rabbit, 26 weeks) and 10 mg/kg/day (dog, 52 weeks) were the no-observed adverse effect level (NOAEL). No toxicological target organs were detected. Four week intravenous toxicity studies with ambroxol hydrochloride in rats (4, 16 and 64 mg/kg/day) and in dogs (45, 90 and 120 mg/kg/day (infusion 3 h/day)) showed no severe local and systemic toxicity including histopathology. All adverse effects were reversible.
Ambroxol hydrochloride was neither embryotoxic nor teratogenic when tested at oral doses up to 3000 mg/kg/day in rats and up to 200 mg/kg/day in rabbits. The fertility of male and female rats was not affected up to 500 mg/kg/day. The NOAEL in the peri- and post-natal development study was 50 mg/kg/day.
At 500 mg/kg/day, ambroxol hydrochloride was slightly toxic for dams and pups, as shown by a retarded body-weight development and reduced litter size.
Genotoxicity studies in vitro (Ames and chromosome aberration test) and in vivo (mouse micronucleus test) did not reveal any mutagenic potential of ambroxol hydrochloride.
Ambroxol hydrochloride did not show any tumorigenic potential in carcinogenicity studies in mice (50, 200 and 800 mg/kg/day) and rats (65, 250 and 1000 mg/kg/day) when treated with a dietary admixture for 105 and 116 weeks, respectively.
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