Four Aspergillus fumigatus species are inhibited by fluconazole, with an IC50 of 23.9–43.5 μg/mL. In serum-supplemented media, Candida albicans' mycelial stage development and germ tube elongation are strongly inhibited by fluconazole (0.20 μg/mL) [1]. Fluconazole is a triazole antifungal medication that prevents infections brought on by Cryptococcus and Candida. The greatest MIC90 (MIC > 64 μg/mL) is seen against Candida krusei and Candida glabrata (MIC ≥ 32 μg/mL). For the following species of Candida, the MIC is less than 2 μg/mL: C. 0.5 μg/mL of albicans, C. 2 μg/mL parapsilosis, C. C. tropicalis (2 μg/mL). C. lusitaniae (2 μg/mL). 0.5 μg/mL of kefyr [2]. The drug fluconazole (0.1–50.0 μg/mL) kills and diminishes the viability of fungus cells [3].

In a mouse model of systemic candidiasis, fluconazole (0, 0.5, 1, 2.5, 5, 7.5, and 10 mg/kg; intraperitoneal (ip) single dose) reduced fungal density (ED50) by 50% to 4.87 mg/kg[4]. Fluconazole has a 2.4-hour terminal elimination half-life following intraperitoneal injection. The amount of fluconazole given has no effect on the terminal half-life [4].

Cell Viability Assay[3]
Cell Types: C.albicans yeast cells (strain ATCC 26310 and strain TW)
Tested Concentrations: 0.1, 0.5, 5.0, 50.0 μg/mL
Incubation Duration: 24 hrs (hours)
Experimental Results: The MICs against both strains were 0.5 μg/ mL.

Animal/Disease Models: Female NYLAR mice (weight, 18 to 20 g; infected intravenously (iv)with C. albicans blastoconidia)[4]
Doses: 5, 10, 15 and 20 mg/kg (pharmacokinetic/PK Analysis)
Route of Administration: Given ip as a single dose
Experimental Results: T1/2=2.4 h

Absorption, Distribution and Excretion
The pharmacokinetic properties of fluconazole are comparable after administration by the intravenous (IV) and oral (PO) routes. In healthy volunteers, the bioavailability of orally administered fluconazole is measured to be above 90%. It is extensively absorbed in the gastrointestinal tract when an oral dose is taken. Oral absorption is not affected by food intake with fluconazole but may increase the time until the maximum concentration is reached. Tmax (or the time taken to achieve the maximum concentration) in one clinical study of healthy patients receiving 50 mg/kg of fluconazole was 3 hours. Peak plasma concentrations (Cmax) in fasting and healthy volunteers occur between 1-2 hours post-dose. Steady-state concentrations are achieved within 5 to 10 days after oral doses of 50-400 mg administered once daily. Administration of a loading dose on the first day of fluconazole treatment, or twice the usual daily dose, leads to plasma concentrations close to steady-state by the second day. Mean AUC (area under the curve) was 20.3 in healthy volunteers receiving 25 mg of fluconazole. **A note on the capsule and powder form and malabsorption syndromes** The capsule forms of fluconazole often contain lactose and should not be administered with hereditary galactose intolerance, _Lapp lactase enzyme_ deficiency, or malabsorption of glucose/galactose. The powder form, used for the oral suspension, lists sucrose as an ingredient and should not be used in patients who have been diagnosed with fructose, glucose/galactose malabsorption, and _sucrase-isomaltase_ enzyme deficiency.
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose measured in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.. A study of a 50mg radiolabeled dose of fluconazole revealed that 93.3% of the dose was found excreted in the urine. **A note on renal failure** The pharmacokinetics of fluconazole are significantly affected by renal dysfunction. The dose of fluconazole may need to be reduced in patients with decreased renal function. A 3-hour hemodialysis treatment lowers plasma fluconazole concentrations by about 50%.
The apparent volume of distribution is said to be similar to the volume of distribution of total body water. One clinical study of healthy volunteers administered 50 mg/kg of fluconazole was 39L, based on a body weight of 60kg. Fluconazole shows substantial penetration in many body fluids, which is a property that renders it an ideal treatment for systemic fungal infections, especially when administered over a longer time. Fluconazole is found in high concentrations in the stratum corneum and dermis-epidermis of skin, in addition to eccrine sweat. Fluconazole is found to accumulate especially well in the stratum corneum, which is beneficial in superficial fungal infections. Saliva and sputum concentrations of fluconazole are found to be similar to the plasma concentrations. In patients diagnosed with fungal meningitis, fluconazole CSF (cerebrospinal fluid) levels are measured to be about 80% of the corresponding plasma levels. Therefore, fluconazole crosses the blood-brain barrier. The meninges are increasingly permeable to fluconazole in states of inflammation, facilitating treatment in meningitis.
This drug is mainly eliminated by the kidneys and the mean body clearance in adults is reported to be 0.23 mL/min/kg. One clinical study of healthy subjects showed total clearance of 19.5 ± 4.7 mL/min and renal clearance of 14.7 ± 3.7 mL/min (1.17 ± 0.28 and 0.88 ± 0.22 L/h). Clearance in the pediatric population varies according to age, as does clearance in patients with renal failure.
The pharmacokinetics of fluconazole are similar following IV or oral administration. The drug is rapidly and almost completely absorbed from the GI tract, and there is no evidence of first-pass metabolism. Oral bioavailability of fluconazole exceeds 90% in healthy, fasting adults; peak plasma concentrations of the drug generally are attained within 1-2 hours after oral administration. ... The rate and extent of GI absorption of fluconazole are not affected by food. The manufacturer states that the commercially available fluconazole suspensions are bioequivalent to the 100-mg fluconazole tablets.
Peak plasma fluconazole concentrations and AUCs increase in proportion to the dose over the oral dosage range of 50-400 mg. Steady-state plasma concentrations of fluconazole are attained within 5-10 days following oral doses of 50-400 mg given once daily. ... When fluconazole therapy is initiated with a single loading dose equal to twice the usual daily dosage and followed by the usual dosage given once daily thereafter, plasma concentrations of the drug reportedly approach steady state by the second day of therapy.
In healthy, fasting adults who received a single 1-mg/kg oral dose of fluconazole, peak plasma concentrations of the drug averaged 1.4 mcg/mL. Following oral administration of a single 400-mg dose of fluconazole in healthy, fasting adults, peak plasma concentrations average 6.72 mcg/mL (range: 4.12-8.1 mcg/mL).
In healthy adults receiving 50- or 100-mg doses of fluconazole given once daily by IV infusion over 30 minutes, serum concentrations of the drug 1 hour after dosing on the sixth or seventh day of therapy ranged from 2.14-2.81 or 3.86-4.96 mcg/mL, respectively.
For more Absorption, Distribution and Excretion (Complete) data for FLUCONAZOLE (14 total), please visit the HSDB record page.

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Metabolism / Metabolites
Fluconazole is metabolized minimally in the liver. Fluconazole is an inhibitor of CYP2C9, CYP3A4 and CYP2C19. Two metabolites were detected in the urine of healthy volunteers taking a 50 mg radiolabeled dose of fluconazole; a glucuronidated metabolite on the hydroxyl moiety (6.5%) and a fluconazole N-oxide metabolite (2%). The same study indicated that no signs of metabolic cleavage of fluconazole were observed, suggesting a difference in metabolism when compared to other agents in the same drug class, which are heavily metabolized in the liver.
Hepatic accounts for <10% of elimination
Hepatic
Route of Elimination: In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug.
Half Life: 30 hours (range 20-50 hours)

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Biological Half-Life
The terminal elimination half-life in the plasma is approximately 30 hours (range: 20-50 hours) after oral administration. The long plasma elimination half-life supports a single-dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications. Patients with renal failure may require dosage adjustment, and half-life can be significantly increased in these patients.
The plasma elimination half-life of fluconazole in adults with normal renal function is approximately 30 hours (range: 20-50 hours). In one study, plasma elimination half-life of the drug was 22 hours after the first day of therapy and 23.8 and 28.6 hours after 7 and 26 days of therapy, respectively.
In a limited, single-dose study in HIV-infected adults, the plasma elimination half-life of fluconazole averaged 32 hours (range: 25-42 hours) in those with absolute helper/inducer (CD4+, T4+) T-cell counts greater than 200 cu m and 50 hours (range: 32-69 hours) in those with CD4+ T-cell counts less than 200 cu m. In other single-dose studies in a limited number of HIV-infected adults with CD4+ T-cell counts less than 200 cu m, the plasma elimination half-life of the drug averaged 35-40 hours (range 22-75 hours).
The mean plasma half-life of fluconazole in children 9 months to 15 years of age has ranged from about 15-25 hours. In a limited study in premature neonates who received IV fluconazole once every 72 hours, the plasma half-life decreased over time, averaging 88 hours after the first dose and 55 hours after the fifth dose (day 13).

Toxicity Summary
Fluconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Fluconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis.

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Interactions
Concurrent use of fluconazole and short-acting benzodiazepines, such as midazolam, may increase the concentration of the benzodiazepine and increase the psychomotor effects; consider decreasing the benzodiazepine dose and monitor the patient carefully for signs of increased benzodiazepine exposure.
Concurrent use of fluconazole and/or itraconazole with tolbutamide, chlorpropamide, glyburide, or glipizide has increased the plasma concentrations of these sulfonylurea agents; hypoglycemia has been noted; blood glucose concentrations should be monitored, and the dose of the oral hypoglycemic agent may need to be reduced.
... In a small study, fluconazole was given with terfenadine and a small pharmacokinetic interaction was found; although no change in cardiac repolarization or accumulation of parent terfenadine was found, concurrent use of terfenadine with fluconazole at doses of 400 mg or greater per day is contraindicated.
Concurrent use of cisapride with fluconazole ... is contraindicated; concurrent use of this antifungal may inhibit the cytochrome P450 enzyme metabolic pathways, resulting in elevated plasma concentrations of cisapride ; this has led to ventricular arrhythmias, including torsades de pointes and QT prolongation ...
For more Interactions (Complete) data for FLUCONAZOLE (17 total), please visit the HSDB record page.

[1]. [In vitro activity of fluconazole, a novel bistriazole antifungal agent]. Jpn J Antibiot. 1989 Jan;42(1):1-16.

[2]. Interpretive breakpoints for fluconazole and Candida revisited: a blueprint for the future of antifungal susceptibility testing. Clin Microbiol Rev. 2006 Apr;19(2):435-47.

[3]. Effect of fluconazole on viability of Candida albicans over extended periods of time. Antimicrob Agents Chemother. 1996 Nov;40(11):2622-5.

[4]. Pharmacodynamics of fluconazole in a murine model of systemic candidiasis. Antimicrob Agents Chemother. 1998 May;42(5):1105-9.

Therapeutic Uses
Mesh Heading: Antifungal agents
MEDICATION: Antifungal; Orally active bistriazole antifungal agent
MEDICATION (VET): Used to treat systemic mycoses, particularly CNS-related conditions in dogs.
Fluconazole ... /is/ indicated for the prophylaxis of febrile neutropenia in patients with hematologic malignancies. /NOT included in US product labeling/
For more Therapeutic Uses (Complete) data for FLUCONAZOLE (16 total), please visit the HSDB record page.

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Drug Warnings
Although serious adverse hepatic effects have been reported only rarely with fluconazole, the possibility that these effects may occur during fluconazole therapy should be considered. Fluconazole therapy should be discontinued if signs and symptoms consistent with liver disease develop. If abnormal liver function test results occur during fluconazole therapy, the patient should be monitored for the development of more severe hepatic injury.
Serious hepatic reactions (eg, necrosis, clinical hepatitis, cholestasis, fulminant hepatic failure) have been reported rarely in patients receiving fluconazole therapy. The manufacturer states that a clear relationship between these hepatic effects and daily dosage, duration of therapy, gender, or age has not been demonstrated. While hepatotoxicity usually has been reversible, fatalities have been reported. Fatalities principally have occurred in patients with serious underlying disease (eg, AIDS, malignancy) who were receiving fluconazole concomitantly with other drugs; however, at least one fatality involved an immunocompetent geriatric individual with renal impairment who developed fulminant hepatic necrosis within 10 days after fluconazole therapy was initiated.
Mild, transient increases (1.5-3 times the upper limit of normal) in serum concentrations of AST (SGOT), ALT (SGPT), alkaline phosphatase, gamma-glutamyltransferase (GGT, gamma-glutamyl transpeptidase, GGTP), and bilirubin have been reported in about 5-7% of patients receiving fluconazole. In most reported cases, concentrations returned to pretreatment levels either during or after fluconazole therapy and were not associated with hepatotoxicity. However, higher increases in serum transaminase concentrations (8 or more times the upper limit of normal), which required discontinuance of the drug, have been reported in about 1% of patients receiving fluconazole. Any patient who develops abnormal liver function test results while receiving fluconazole should be closely monitored for the development of more severe hepatic injury.
Because potentially fatal exfoliative skin disorders have been reported rarely in patients with a serious underlying disease receiving fluconazole, the possibility that these effects can occur should be considered. Immunocompromised patients (e.g., patients with HIV infections) who develop rash during fluconazole therapy should be monitored closely and the drug discontinued if the lesions progress.
For more Drug Warnings (Complete) data for FLUCONAZOLE (17 total), please visit the HSDB record page.

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Pharmacodynamics
Fluconazole has been demonstrated to show fungistatic activity against the majority of strains of the following microorganisms, curing fungal infections: _Candida albicans, Candida glabrata (Many strains are intermediately susceptible), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans_ This is achieved through steroidal inhibition in fungal cells, interfering with cell wall synthesis and growth as well as cell adhesion, thereby treating fungal infections and their symptoms. The fungistatic activity of fluconazole has also been shown in normal and immunocompromised animal models with both systemic and intracranial fungal infections caused by _Cryptococcus neoformans_ and for systemic infections caused by Candida albicans. It is important to note that resistant organisms have been found against various strains of organisms treated with fluconazole. This further substantiates the need to perform susceptibility testing when fluconazole is considered as an antifungal therapy. **A note on steroidal effects of fluconazole** There has been some concern that fluconazole may interfere with and inactivate human steroids/hormones due to the inhibition of hepatic cytochrome enzymes. Fluconazole has demonstrated to be more selective for _fungal_ cytochrome P-450 enzymes than for a variety of mammalian cytochrome P-450 enzymes. Fluconazole 50 mg administered daily for up to 28 days in individuals of reproductive age has been show to have no effect on testosterone plasma concentrations of males and plasma concentrations of steroids in females. A 200-400 mg dose of fluconazole showed no clinically relevant effect on steroid levels or on ACTH-stimulated steroid response in healthy males, in one clinical study mentioned on the European Medicines Agency label. Other studies have shown no significant effects of fluconazole on steroid levels, further confirming these data.

C13H12F2N6O

306.27

306.104

86386-73-4

Fluconazole-d4;1124197-58-5;Fluconazole hydrate;155347-36-7;Fluconazole mesylate;159532-41-9

3365

White to off-white solid powder

1.5±0.1 g/cm3

579.8±60.0 °C at 760 mmHg

138-140°C

304.4±32.9 °C

0.0±1.7 mmHg at 25°C

1.663

0.5

1

7

5

22

358

0

RFHAOTPXVQNOHP-UHFFFAOYSA-N

InChI=1S/C13H12F2N6O/c14-10-1-2-11(12(15)3-10)13(22,4-20-8-16-6-18-20)5-21-9-17-7-19-21/h1-3,6-9,22H,4-5H2

2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.16 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.16 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.16 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 2 mg/mL (6.53 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)