Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: Antipsoriatics, retinoids for treatment of psoriasis ATC code: D05BB02

Mechanism of action
Retinol (Vitamin A) is known to be essential for normal epithelial growth and differentiation, though the mode of this effect is not yet established. Both retinol and retinoic acid are capable of reversing hyperkeratotic and metaplastic skin changes.
However, these effects are generally only obtained at dosages associated with considerable local or systemic toxicity. Acitretin, a synthetic aromatic derivative of retinoic acid, has a favourable therapeutic ratio, with a greater and more specific 

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inhibitory effect on psoriasis and disorders of epithelial keratinisation. The usual therapeutic response to acitretin consists of desquamation (with or without erythema) followed by more normal re-epithelialisation.

Acitretin is the main active metabolite of etretinate.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
Absorption
Acitretin reaches peak plasma concentration 1 - 4 hours after ingestion of the drug.
Bioavailability of orally administered acitretin is enhanced by food. Bioavailability of a single dose is approximately 60%, but inter-patient variability is considerable (36 - 95%).

Distribution
Acitretin is highly lipophilic and penetrates readily into body tissues. Protein binding of acitretin exceeds 99%. In animal studies, acitretin passed the placental barrier in quantities sufficient to produce foetal malformations. Due to its lipophilic nature, it can be assumed that acitretin passes into breast milk in considerable quantities.

Biotransformation
Acitretin is metabolised by isomerisation into its 13-cis isomer (cis acitretin), by glucuronidation and cleavage of the side chain.

Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and alcohol. Etretinate is highly teratogenic and has a longer half-life (approximately 120 days) than acitretin (see section 4.4, 4.5 and 4.6).

Elimination
Multiple-dose studies in patients aged 21 - 70 years showed an elimination half-life of approximately 50 hours for acitretin and 60 hours for its main metabolite in plasma, cis acitretin, which is also a teratogen. From the longest elimination half-life observed in these patients for acitretin (96 hours) and cis acitretin (123 hours), and assuming linear kinetics, it can be predicted that more than 99% of the drug is eliminated within 36 days after cessation of long-term therapy. Furthermore, plasma concentrations of acitretin and cis acitretin dropped below the sensitivity limit of the assay (< 6ng/ml) within 36 days following cessation of treatment. Acitretin is excreted entirely in the form of its metabolites, in approximately equal parts via the kidneys and the bile.