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Pharmacology: Mechanism of Action: Administered orally, isotretinoin has a marked effect in severe forms of acne, which have proved insufficiently responsive to previous treatment. The mechanism of action of isotretinoin has not yet been elucidated in detail, but it has been established that the improvement observed in the clinical picture of severe acne is associated with dose-related suppression of sebaceous gland activity and a histologically demonstrated reduction in the size of the sebaceous glands. Furthermore, a dermal anti-inflammatory effect of isotretinoin has been established.
Pharmacokinetics: Time-related blood concentrations can be predicted on the basis of linear pharmacokinetics.
Absorption: Peak plasma concentrations (Cmax) of approximately 200-300 ng/ml have been achieved in healthy volunteers three to four hours (tmax) after administration of 40 mg isotretinoin.
Taking isotretinoin with food increases bioavailability up to twofold relative to fasting conditions, probably as a result of easier absorption of this highly lipophilic medication. Furthermore, there is an overall decrease in fluctuations in systemic availability when isotretinoin is ingested with food.
Distribution: Isotretinoin is extensively bound to plasma proteins (99.9%) with the result that the free active fraction of the substance is less than 0.1% of the total over a wide range of therapeutic concentrations. Albumin appears to be the major binding protein.
The volume of distribution of isotretinoin is not known in humans since it is not available as an intravenous preparation.
Metabolism: Three major metabolites have been identified in plasma: 4-oxo-isotretinoin, tretinoin (all-trans retinoic acid), and 4-oxo-tretinoin. The major blood metabolite of isotretinoin is 4-oxo-isotretinoin, which is rapidly formed following oral administration achieving peak concentrations of 100 - 140 ng/ml at about two hours after administration of 40 mg isotretinoin. Other minor metabolites have been detected but are not completely identified, which also includes glucuronide conjugates.
Isotretinoin metabolites have shown biological activity in several in-vitro tests. Thus the observed clinical profile in patients could be the result of the pharmacological activity of isotretinoin and its metabolites.
Since isotretinoin and tretinoin (all-trans retinoic acid) are reversibly metabolised (= interconverted), the metabolism of tretinoin is linked with that of isotretinoin. It has been estimated that 20-30% of an isotretinoin dose is metabolised by isomerization.
Isotretinoin also isomerises in vivo via an alternative metabolic pathway to tretinoin (all-trans retinoic acid). Glucuronidation of the metabolites has not been conclusively demonstrated in humans but is strongly suggested by animal studies. Investigations in humans and dogs point to an enterohepatic recirculation of isotretinoin, which would contribute to the observed interindividual variability in plasma concentrations.
In vitro metabolism studies have demonstrated that several CYP enzymes are involved in the metabolism of isotretinoin to 4-oxo-isotretinoin and tretinoin. No single isoform appears to have a predominant role. CYP2C8, CYP2C9, CYP2B6, and possibly CYP3A4 appear to have the greatest contributions in the metabolism of isotretinoin to 4-oxo-isotretinoin. CYP2C9, CYP2B6, and possibly CYP2C8, CYP3A4, CYP2A6, and CYP2E1 contribute to the metabolism of isotretinoin. CYP 26 is also known to metabolize retinoids.
Elimination: Isotretinoin appears to be eliminated almost exclusively by hepatic metabolism and biliary excretion.
Following oral administration of isotretinoin, the elimination half-life of unchanged substance has ranged from 7 to 39 hours (mean approximately 20 hours) in both healthy volunteers and patients with cystic acne.
The mean elimination half-life of the 4-oxo metabolite in patients with cystic acne is slightly longer (25 hours, range: 17-50 hours) than that of the parent substance.
Isotretinoin is a physiological retinoid and endogenous retinoid concentrations are reached within approximately two weeks following the end of isotretinoin therapy.
Special Populations: Since isotretinoin is contraindicated in patient's hepatic impairment, there is no information on the pharmacokinetics of the substance in this population.
Patients with Renal Impairment: In patients with severe renal insufficiency treatment should be started at a lower dose (e.g. 10 mg/day) and afterwards individually adjusted according to tolerability.
