Since the kinetics of isotretinoin and its metabolites is linear, its concentration in the plasma during therapy can be predicted on the basis of the data obtained after a single administration. This property of the drug is also said that it does not affect the activity of liver enzymes involved in the metabolism of drugs. Absorption Absorption of isotretinoin from the gastrointestinal tract varies. The gerald andriole absolute bioavailability of isotretinoin has not been determined, since the release form of the drug for intravenous use in humans there. However, extrapolation of data obtained in an experiment on dogs, suggesting a rather low and variable bioavailability system.
In patients with acne maximum plasma concentration in an equilibrium state after administration of 310 mg of 80 ng / ml, fasting isotretinoin (range 188-473 ng / ml) were achieved after 2-4 hours. Concentrations of isotretinoin in plasma is about 1.7 times higher than the concentrations in the blood due to poor penetration of isotretinoin in erythrocytes. Isotretinoin with food increases bioavailability by 2 times compared with the reception of an empty stomach. Distribution Isotretinoin a large extent (99.9%) bound to plasma proteins, mainly manner to albumin, so that a wide range of therapeutic concentrations content of free (pharmacologically active) fraction of the drug is less than 0.1% of the total. The volume of isotretinoin distribution in humans is not determined as a dosage form for intravenous administration exists. Equilibrium isotretinoin concentration in blood ( Cmin ss) in patients with severe acne treated with 40 mg 2 times a day, ranged from 120 to 200 ng / mL.concentrations of 4-oxo-isotretinoin in these patients is 2.5 times higher than those of isotretinoin. Data on the penetration of isotretinoin into tissue in humans is not enough. Concentrations of isotretinoin in the epidermis is two times lower than in serum.
Metabolism After ingestion plasma detected three main metabolite , tretinoin (all transretinoevaya acid) and 4-oxo-retinoin. The main metabolite is, plasma concentration at steady state is 2.5 times higher than the concentration of the parent drug. Found less significant metabolites including gerald andriole glucuronides as, but not all the installed structure metabolites. The metabolites of isotretinoin have biological activity confirmed in several laboratory tests. Thus, the clinical effects of the drug in patients can result from the pharmacological activity of isotretinoin and its metabolites. Since in vivo tretinoin and isotretinoin (fully transretinoevaya acid) reversibly transformed into each other, associated with the metabolism of tretinoin isotretinoin metabolism. 20-30% of the dose is metabolized by isomerization of isotretinoin.
The pharmacokinetics of isotretinoin in man an essential role can play enterohepatic circulation. In vitro, metabolism Studies have shown that multiple enzyme system cytochrome are involved in the conversion of isotretinoin and tretinoin. Apparently, none of the isoforms while not playing the dominant role. and its metabolites do not significantly affect the activity of the enzyme system. Excretion After oral administration of radiolabeled isotretinoin in the urine and faeces is found in approximately the same amount. The half-life of terminal phase of unchanged drug in patients with acne is an average of 19 hours. The half-life of terminal phase of the 4-oxo-isotretinoin, apparently, more and equal to an average of 29 hours. Isotretinoin relates to natural (physiological) retinoids. The endogenous retinoid concentrations are restored after about 2 weeks after discontinuation .
Pharmacokinetics in special clinical situations
Since isotretinoin is contraindicated in liver dysfunction, the data on the pharmacokinetics of the drug in this group of patients is limited. Renal insufficiency does not affect the pharmacokinetics of isotretinoin.
Severe forms of acne (nodular or cystic, conglobata acne or acne with risk of scarring).
Acne is not amenable to gerald andriole other therapies.
Pregnancy, lactation (see. Section “Pregnancy and breast-feeding”), hepatic failure, hypervitaminosis A, expressed hyperlipidemia, concomitant tetracycline therapy.
Hypersensitivity to the drug or its components (including soybeans).
Children under the age of 12 years.
Depression history, diabetes, obesity, lipid metabolism, alcoholism.
Pregnancy and breast-feeding
Isotretinoin – a drug with a strong teratogenic. If pregnancy occurs during the period when a woman orally takes isotretinoin (at any dose, even for a short time), there is a great danger of having a child with developmental disabilities.
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Is contraindicated in women of childbearing age, if the woman’s condition does not satisfy all of the following criteria:
– it should have a severe form of acne that is resistant to conventional therapies;
– it must accurately understand and follow the instructions of a doctor;
– it should be informed the doctor about the dangers of becoming pregnant during treatment with within one month after he and urgent consultations with suspected pregnancy;
– it must be warned of the possible ineffectiveness of contraceptive use;
– it must confirm that understands the precautions;
– it must understand the need and continuously use effective methods of contraception for one month before treatment with , while treatment and for one month after the end (see. “Interaction with other medicinal products” section); it is desirable to simultaneously use two different methods of contraception, including barrier;
– it must be a negative result is reliable pregnancy test within 11 days prior to taking the drug; pregnancy test is highly recommended monthly during treatment and 5 weeks after the end of treatment;
– it should start treatment with
only 2-3 days the next normal menstrual period;
– it must understand the need for mandatory medical visits each month
– at treatment for recurrent disease it should always use the same effective methods of contraception for one month before starting treatment with gerald andriole, during treatment and for one month after its completion, as well as to pass the same reliable pregnancy test;
– it must fully understand the need for safety precautions and confirm their understanding and desire to use reliable methods of contraception, she explained to the doctor.
the use of contraceptives on these guidelines during treatment with isotretinoin should be recommended even for those women who do not usually use contraceptive methods due to infertility (except patients who have undergone a hysterectomy), amenorrhea, or who reported not to be sexually active
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