International  unpatented name: Fluconazole

 

Composition
Active substance: 1 capsule contains 150 mg of fluconazole.
Excipients: lactose monohydrate, corn starch, magnesium stearate, colloidal silicon

dioxide, sodium lauryl sulfate.

 

Description

The contents are turquoise colored capsules with white to cream colored powder.

 

Pharmacotherapeutic group

Antifungal drug (Triazole derivative). 

ATC code: J02AC01.

 

pharmacological properties

Pharmacodynamics

Fluconazole is a triazole derivative. Fluconazole is a strong and selective inhibitor of fungal cell sterol synthesis, and has a specific effect on cytochrome P(450)-dependent enzymes. Flucosal is an antifungal drug with a broad spectrum of action.  Component  especially for different types of Candida (Candida albicans, Candida parapsilosis, Candida tropicalis, Candida dubliniensis, Candida guilliermondii, Candida kefir, Candida lusitaniae) and Cryptococci (Cryptococcus_cc781905 -3194-bb3b-136bad5cf58d_ active against neformans).

Candida krusei is resistant to fluconazole, Candida glabrata is less sensitive. Aspergillus spp. It is resistant to fluconazole. Fluconazole has been shown to be effective in endemic mycoses, including Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum.

Fluconazole  has high specificity against fungal enzymes dependent on the cytochrome P450 system. Therapy with fluconazole at a dose of 50 mg/day for 28 days  does not affect the concentration of testosterone in blood plasma in men and steroids in the reproductive period in women. Fluconazole at a dose of 200–400 mg/day has no significant effect on endogenous steroids and their effects on ACTH in such healthy men.

The mechanism of development of resistance to fluconazole

Resistance to fluconazole develops in the following cases:

- Qualitative and quantitative changes in the target enzyme for fluconazole (lanosteril-14-α-demethylase)

- Reduce the access of fluconazole to the target

- Combination of both mechanisms

Mutations in the ERG11 gene encoding target-enzymes lead to structural changes of the target and reduced affinity for azoles. Increased ERG11 gene expression leads to higher concentrations of target enzymes. In order to weaken the activity of all enzyme molecules in this cell, it requires an increase in the concentration of fluconazole inside the cell.

The second main mechanism of resistance is carried out by the removal of fluconazole from the cell with two types of activated transporters (transporters). These transporters include the first mediator (MDR), which encodes genes for multidrug resistance, and the superclass ATF linker  transporters (CDR), which encodes resistance genes of Candida fungi. Hyperexpression of the MDR gene causes resistance to fluconazole. At the same time, hyperexpression of CDR genes  causes resistance to various azoles.

Resistance against Candida glabrata usually develops from hyperexpression of the CDR gene.   The minimally inhibited concentration (16-32 mcg/ml) is considered as the maximum dose of fluconazole in some strains. Candida krusei is resistant to fluconazole. The mechanism of development of resistance is related to the reduced sensitivity of the target enzyme to the inhibitory effect of fluconazole.

Pharmacokinetics

Fluconazole is easily absorbed after oral administration, its concentration (and total biological value) in blood plasma exceeds 90%. Food intake does not affect the absorption of fluconazole. The concentration in the blood plasma corresponds to the dose, and Tmax when taken before meals is 0.5-1.5 hours, and T1/2 is about 30 hours. Css  -90% -a terapiyanın başlanmasından 4-5 gün sonra çatır       _cc781905 -5cde-3194-bb3b-136bad5cf58d_       (in multiple intakes of the preparation 1 time per day). Tmax at internal reception is 4 hours. Taking 2 times the maximum dose (day 1)   on the 2nd day of therapy   causes 90% Css. Vd is close to the total level of water in the body. It combines 11-12% with blood plasma proteins.

Fluconazole easily enters body fluids. The concentration in saliva, sputum and blood plasma is the same.

In fungal meningitis, the concentration of flucanazole in the spinal fluid is 80% of the plasma concentration. Its concentration in the cornea, epidermis, skin and sweat exceeds the plasma level. When taking flukanazol in a dose of 50 mg   once a day, its concentration in the cornea is 73 mcg/g after 12 days, and after 7 days - 5.8 mcg/g. . At a dose of 150 mg once a week, the concentration of flukanazol in the cornea  is 23.4 μg/g on the 7th day, and 7.1 μg/g 7 days after the second dose. After taking fluconazole 150 mg once a week on a healthy  nail plate  for 4 months  and on damaged nail plate 4.0 .8 μg/g. 6 months after the end of therapy, the level of fluconazole in the nail plate does not change.

The drug is mainly excreted by the kidneys - 80% of the dose is excreted unchanged in the urine. Fluconazole clearance is proportional to creatinine clearance. Metabolites were not detected in the blood. Having a long half-life allows fluconazole to be taken daily or once a week in vaginal candidiasis   and other diseases

Special pharmacokinetics in children

The following pharmacokinetic data are reflected in children [mean value (% change, coefficient)].