The drug for the treatment of acne, retinoids. Isotretinoin, the active ingredient of the drug Roaccutane is a stereoisomer of all-trans retinoic acid (tretinoin).
The exact mechanism of action Roaccutane not yet been elucidated, but found that the improvement of the clinical picture of severe acne is associated with suppression of sebaceous glands and histologically confirmed by a decrease in their size. In addition, the proven anti-inflammatory effect of isotretinoin on the skin.
Hyperkeratosis epithelial cells in hair follicles and sebaceous glands leads to peeling korneotsitov in duct cancer and occlusion of the last keratin and excess sebaceous secretion. This is followed by the formation of comedones and, in some cases, the accession of the inflammatory process. Roaccutane sebotsitov inhibits proliferation and acts on acne, restoring the normal process of cell differentiation. Sebum – the main substrate for the growth of Propionibacterium acnes, thus reducing the production of sebum suppresses bacterial colonization of the duct.
Since the kinetics of isotretinoin and its metabolites is linear, the level of its concentration in plasma during therapy can be predicted on the basis of data obtained after single dose. It also demonstrates that isotretinoin has no effect on the activity of hepatic enzymes involved in the metabolism of drugs.
Absorption
The absorption of isotretinoin from the gastrointestinal tract varies. The absolute bioavailability of isotretinoin has not been determined, since the release forms of drugs for in / No human use. However, extrapolating data obtained in experimental animal studies, suggests quite low and variable systemic bioavailability. In patients with acne Cmax after administration of 80 mg of isotretinoin on an empty stomach was 310 ng / ml (range 188-473 ng / ml) was achieved in 2-4 h. The concentrations of isotretinoin in plasma at about 1.7 times higher than concentrations in the blood due to poor penetration of isotretinoin erythrocytes. Acceptance of isotretinoin with food increases the bioavailability of 2 times compared with the reception of an empty stomach.
Distribution
Isotretinoin is in a strong degree (99.9%) bound to plasma proteins, primarily albumin, so that a wide range of therapeutic concentrations of free (pharmacologically active) fraction of the drug is less than 0.1% of the total. Vd isotretinoin is not defined as dosage form for a / in the introduction does not exist. Cssmin isotretinoin in patients with severe acne who received the drug at 40 mg 2 times ranged from 120 to 200 ng / ml. Concentrations of 4-oxo-isotretinoin in these patients is 2.5 times greater than those of isotretinoin. Data on the penetration of isotretinoin into tissue in humans is not enough. Concentrations of isotretinoin in the epidermis in 2 times lower than in serum.
Metabolism
Once inside the plasma found three major metabolites: 4-oxo-isotretinoin, tretinoin (all-trans-retinoic acid) and 4-oxo-retinoin. The main metabolite is 4-oxo-isotretinoin, plasma concentrations of which in the equilibrium state is 2.5 times higher than the initial concentration of the drug. Detected and less significant metabolites, which also include glucuronide, but not all, establishing the structure of metabolites.
The metabolites of isotretinoin have biological activity, confirmed in several laboratory tests. Thus, the clinical effects of the drug may be the result of pharmacological activity of isotretinoin and its metabolites. Because in vivo isotretinoin and tretinoin (all-trans-retinoic acid) reversibly transformed into each other, tretinoin metabolism is linked to the metabolism of isotretinoin. 20-30% of the dose of isotretinoin is metabolized by isomerization. In the pharmacokinetics of isotretinoin in humans may play a significant role enterohepatic circulation. Studies of metabolism in vitro have shown that in the transformation of isotretinoin to 4-oxo-isotretinoin and tretinoin involving several enzymes CYP. Apparently, none of the isoforms at the same time does not play a dominant role, but the most important in the metabolism of isotretinoin to 4-oxo-isotretinoin play CYP 2C8, CYP 2C9, CYP 2B6, and probably, CYP 3A4. In the metabolism of isotretinoin are also involved CYP 2A6 and CYP 2E1. It is known that CYP 26 also can metabolize retinoids.
Withdrawal
After oral administration of radioactively labeled with isotretinoin in the urine and feces revealed approximately the same amount. T1 / 2 terminal phase for the unchanged drug in patients with acne is an average of 19 hours T1 / 2 terminal phase for the 4-oxo-isotretinoin, apparently, more and makes an average of 29 hours Isotretinoin belongs to the natural (physiological) retinoids. The endogenous concentration of retinoids recovered in about 2 weeks after receiving Roaccutane. Pharmacokinetics in special clinical situations Since isotretinoin is contraindicated in abnormal liver function, data on the pharmacokinetics of the drug in this group of patients is limited.
Indications for use of the drug Roaccutane
- Severe nodulocystica acne not amenable to other forms of therapy.
