General
Preferred name
FLUCONAZOLE
Synonyms
Fluconazole (mesylate) ()
Fluconazole (hydrate) ()
UK 49858 mesylate ()
UK 49858 hydrate ()
UK-49858 ()
Fluconazole86386-73-4 ()
Fluconazole (UK 49858) ()
Diflucan, Trican, Alfumet,UK 49858 ()
Fluconazole mesylate ()
Fluconazole hydrate ()
BAYT-006267 ()
UK-49,858 ()
Canesten Oral ()
Diflucan One ()
NSC-758661 ()
Difluconazole ()
Fluconazole In Sodium Chloride ()
Alkanazole ()
Triflucan ()
BAYT006267 ()
Fluconazoli ()
Diflucan ()
Zoltec ()
Diflucan In Sodium Chloride ()
Fluconazole-d4 ()
P&D ID
PD000782
CAS
86386-73-4
159532-41-9
155347-36-7
1124197-58-5
Tags
available
drug
Approved by
FDA
First approval
1990
Drug Status
investigational
approved
Drug indication
Antifungal
Fungal infection
Max Phase
Phase 4
Structure
Probe scores
P&D probe-likeness score
[[ v.score ]]%
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
MOA Fluconazole is a very selective inhibitor of fungal cytochrome P450 dependent enzyme _lanosterol 14-α-demethylase_. This enzyme works to convert _lanosterol_ to _ergosterol_, which is necessary for fungal cell wall synthesis. Specifically, the free nitrogen atom of the azole ring of fluconazole binds an iron atom within the heme group of the enzyme. This prevents the activation of oxygen and, as a result, the demethylation of lanosterol, which stops the process of ergosterol biosynthesis. Methylated sterols accumulate in the fungal cellular membrane, resulting in an arrest of fungal cell growth [A174349]. Fluconazole resistance may arise from an alteration in the quality or quantity of the target enzyme (lanosterol 14-α-demethylase), reduced access to this target, or a combination of these mechanisms [A16632].
ROE In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose measured in the urine as unchanged drug [FDA label]. About 11% of the dose is excreted in the urine as metabolites [FDA label]. **Renal Failure**: The pharmacokinetics of fluconazole are significantly affected by renal dysfunction. An inverse relationship exists between the elimination half-life and creatinine clearance. The dose of fluconazole may need to be reduced in patients with decreased renal function. A 3-hour hemodialysis treatment decreases plasma fluconazole concentrations by about 50% [FDA label].
HALF-LIFE Approximately 30 hours (range: 20-50 hours) after oral administration [FDA label]. The long plasma elimination half-life supports a single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications [F3250].
TOXICITY **Acute oral toxicity (LD50)**: 1271 mg/kg (rat) [MSDS] **A note on liver toxicity**: The FDA label warns that this drug carries a risk of hepatotoxicity. Rare cases of serious hepatic toxicity have been reported, including fatalities primarily in patients with serious underlying medical conditions using fluconazole. In patients with existing liver dysfunction, use caution when fluconazole is administered. Patients who are found to have abnormal liver function tests during therapy should be carefully monitored for the development of more severe hepatic injury, and fluconazole should be discontinued if it is likely to be the underlying cause of liver injury. **Carcinogenesis, Mutagenesis, and Impairment of Fertility** Fluconazole demonstrated no evidence of carcinogenic risk in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7x the recommended human dose). Male rats administered 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 μg/mL) demonstrated no sign of chromosomal mutations [FDA label]. **Use in Pregnancy**: There are no sufficient and well-controlled studies of fluconazole use in pregnant women. Available human data do not show an increased risk of congenital anomalies after one maternal dose of 150 mg. Several case reports describe a rare pattern of distinct congenital anomalies in infants exposed in-utero to high dose maternal fluconazole (400-800 mg/day) during the majority or all of the first trimester. These reported anomalies are comparable to those seen in animal studies. If this drug is administered during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the possible risks to the fetus [FDA label].
METABOLISM Fluconazole is metabolized in the liver, but only to a minor extent. Fluconazole is a selective inhibitor of the isozymes CYP2C9 and CYP3A4. This drug is also an inhibitor of the isozyme CYP2C19 [F3250].
ABSORPTION The pharmacokinetic properties of fluconazole are comparable after administration by the intravenous and oral routes. In healthy volunteers, the bioavailability of orally administered fluconazole is measured to be above 90%, compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose [FDA label]. Oral absorption is not affected by simultaneous food intake [F3250]. Peak plasma concentrations (Cmax) in fasting and healthy volunteers occur between 1-2 hours post-dose [FDA label]. 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 treatment, of twice the usual daily dose, leads to plasma concentrations close to steady-state by the second day [FDA label].
MOA Fluconazole is a very selective inhibitor of fungal cytochrome P450 dependent enzyme _lanosterol 14-α-demethylase_. This enzyme normally works to convert _lanosterol_ to _ergosterol_, which is necessary for fungal cell wall synthesis. The free nitrogen atom located on the azole ring of fluconazole binds with a single iron atom located in the heme group of lanosterol 14-α-demethylase.[A178774] This prevents oxygen activation and, as a result, inhibits the demethylation of lanosterol, halting the process of ergosterol biosynthesis.[A178777] Methylated sterols are then found to accumulate in the fungal cellular membrane, leading to an arrest of fungal growth.[A178774] These accumulated sterols negatively affect the structure and function of the fungal cell plasma membrane.[A16632]; ; Fluconazole resistance may arise from an alteration in the amount or function of the target enzyme (lanosterol 14-α-demethylase), altered access to this enzyme, or a combination of the above.[A16632] Other mechanisms may also be implicated, and studies are ongoing.[A178783]
METABOLISM Fluconazole is metabolized minimally in the liver. Fluconazole is an inhibitor of CYP2C9, CYP3A4 and CYP2C19.[L6496,FDA label] 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%).[A178813] 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.[A178813,A178834]
HALF-LIFE The terminal elimination half-life in the plasma is approximately 30 hours (range: 20-50 hours) after oral administration.[FDA label]; The long plasma elimination half-life supports a single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications.[L6496]. Patients with renal failure may require dosage adjustment, and half-life can be significantly increased in these patients.[A178792];
PHARMACODYNAMICS Fluconazole has been demonstrated to be active against most strains of the following microorganisms both in vitro and in clinical infections, exhibiting fungistatic effects [FDA label]. This is achieved through steroidal inhibition in fungal cells, interfering with cell wall synthesis and growth, thereby treating fungal infections: _Candida albicans, Candida glabrata (Many strains are intermediately susceptible), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans_ Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for both systemic and intracranial fungal infections due to _Cryptococcus neoformans_ and for systemic infections due to Candida albicans [FDA label]. Some studies suggest that fluconazole may interfere with and inactivate human steroids due to the inhibition of hepatic cytochrome enzymes. However, fluconazole is 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 has been shown not to affect testosterone plasma concentrations of males or steroid concentration in females of reproductive age. Fluconazole 200 mg-400 mg daily exerts no clinically relevant effect on endogenous steroid levels or on ACTH-stimulated response in healthy male subjects [F3250]. Other studies have shown no significant effects of fluconazole on steroid levels [A174355], [A174358].
INDICATION **Fluconazole can be administered in the treatment of the following fungal infections**: Vaginal candidiasis (vaginal yeast infections due to Candida) [FDA label] Oropharyngeal and esophageal candidiasis [FDA label] Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia [FDA label] Cryptococcal meningitis [FDA label]. **Fungal infection prophylaxis**: this drug can be used in the prophylaxis of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy [FDA label] **A note on laboratory testing**: Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) are recommended to be obtained prior to therapy to isolate and identify the causative organism(s). Therapy may be initiated before the results of the cultures and other laboratory studies are returned; however, once these results become available, therapy must be adjusted accordingly [FDA label].
PHARMACODYNAMICS Fluconazole has been demonstrated to show fungistatic activity against the majority of strains of the following microorganisms, curing fungal infections[FDA label]:; ; _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.[FDA label,A174325,A174343]; ; 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.[FDA label] It is important to note that resistant organisms have been found against various strains of organisms treated with fluconazole.[A178759,A178762,A178765] This further substantiates the need to perform susceptibility testing when fluconazole is considered as an antifungal therapy.[A178768,A178786] ; ; ; **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.[L6496] 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.[L6496] Other studies have shown no significant effects of fluconazole on steroid levels, further confirming these data.[A174358,A178780]
INDICATION Fluconazole can be administered in the treatment of the following fungal infections[FDA label]:; ; 1) Vaginal yeast infections caused by Candida; 2) Systemic Candida infections; 3) Both esophageal and oropharyngeal candidiasis ; 4) Cryptococcal meningitis; 5) UTI (urinary tract infection) by Candida; 6) Peritonitis (inflammation of the peritoneum) caused by Candida; ; **A note on fungal infection prophylaxis**; ; Patients receiving bone marrow transplantation who are treated with cytotoxic chemotherapy and/or radiation therapy may be predisposed to candida infections, and may receive fluconazole as prophylactic therapy.[FDA label]; ; **A note on laboratory testing**; ; Obtaining specimens for fungal culture and other important laboratory studies such as serology or pathology is advised before starting fluconazole therapy in order to isolate the organisms to be eliminated through treatment. It is permissible to start therapy before the results are available, however, adjusting the therapy once laboratory results confirm the causative organism may be necessary.[FDA label];
ROE In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose measured in the urine as unchanged drug.[FDA label] About 11% of the dose is excreted in the urine as metabolites.[FDA label]. A study of a 50mg radiolabeled dose of fluconazole revealed that 93.3% of the dose was found excreted in the urine.[A178813]; ; **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%.[FDA label];
ABSORPTION 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%.[FDA label] It is extensively absorbed in the gastrointestinal tract when an oral dose is taken.[A178813] Oral absorption is not affected by food intake with fluconazole but may increase the time until the maximum concentration is reached.[L6496,A178792]; ; 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.[A178792] ; ; Peak plasma concentrations (Cmax) in fasting and healthy volunteers occur between 1-2 hours post-dose.[FDA label] 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.[FDA label] Mean AUC (area under the curve) was 20.3 in healthy volunteers receiving 25 mg of fluconazole.[A178792]; ; **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.[FDA label] 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.[FDA label]
DESCRIPTION High affinity retinol-binding protein 4 (RBP4) ligand (Tocris Bioactive Compound Library)
DESCRIPTION Fluconazole (hydrate) is the hydrate salt form of fluconazole, which is a triazole antifungal intended for oral treatment of superficial and systemic mycoses. In tests done in standard mycological media, the compound had minimal inhibitory concentrations against pathogenic Candida species that were usually in excess of 100 mg/l. Fluconazole inhibited branching and hyphal development in C. albicans at concentrations as low as 10(-6) M (0.3 mg/l), but miconazole and ketoconazole were still active in these tests at concentrations 100 times lower than this. Oral fluconazole was not associated with a significantly increased risk of birth defects overall or of 14 of the 15 specific birth defects of previous concern. Fluconazole exposure may confer an increased risk of tetralogy of Fallot. Fluconazole is predicted to be ineffective against Cryptococcus gattii in the koala as a sole therapeutic agent administered at 10 mg/kg p.o. every 12 h. (BOC Sciences Bioactive Compounds)
DESCRIPTION Fluconazole (mesylate) is the mesylate salt form of fluconazole, which is a triazole antifungal intended for oral treatment of superficial and systemic mycoses. In tests done in standard mycological media, the compound had minimal inhibitory concentrations against pathogenic Candida species that were usually in excess of 100 mg/l. Fluconazole inhibited branching and hyphal development in C. albicans at concentrations as low as 10(-6) M (0.3 mg/l), but miconazole and ketoconazole were still active in these tests at concentrations 100 times lower than this. Oral fluconazole was not associated with a significantly increased risk of birth defects overall or of 14 of the 15 specific birth defects of previous concern. Fluconazole exposure may confer an increased risk of tetralogy of Fallot. Fluconazole is predicted to be ineffective against Cryptococcus gattii in the koala as a sole therapeutic agent administered at 10 mg/kg p.o. every 12 h. (BOC Sciences Bioactive Compounds)
Cell lines
0
Organisms
11
Compound Sets
27
Axon Medchem Screening Library
2105
BOC Sciences Bioactive Compounds
fluconazole-mesylate-cas-159532-41-9-item-84-463550
fluconazole-hydrate-cas-155347-36-7-item-84-463544
Cayman Chemical Bioactives
11594
18252
ChEMBL Approved Drugs
CHEMBL106
ChEMBL Drugs
CHEMBL106
Drug Repurposing Hub
DrugBank
DB00196
DrugBank Approved Drugs
DB00196
DrugCentral
1187
DrugCentral Approved Drugs
1187
DrugMAP
DMOWZ6B
DrugMAP Approved Drugs
DMOWZ6B
DrugMatrix
Enamine BioReference Compounds
LSP-MoA library (Laboratory of Systems Pharmacology)
CHEMBL106
MedChem Express Bioactive Compound Library
HY-B0101
NCATS Inxight Approved Drugs
8VZV102JFY
NIH Clinical Collections (NCC)
NPC Screening Collection
Pandemic Response Box
Prestwick Chemical Library
ReFrame library
Selleckchem Bioactive Compound Library
Fluconazole
TargetMol Bioactive Compound Library
T1388
The Spectrum Collection
Tocris Bioactive Compound Library
3764
ZINC Tool Compounds
ZINC000000004009
External IDs
59
Properties
(calculated by RDKit )
Molecular Weight
306.1
Hydrogen Bond Acceptors
7
Hydrogen Bond Donors
1
Rotatable Bonds
5
Ring Count
3
Aromatic Ring Count
3
cLogP
0.74
TPSA
81.65
Fraction CSP3
0.23
Chiral centers
0.0
Largest ring
6.0
QED
0.75
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target
Fungal
14-?? Demethylase
CYP51A1
Antifungal agent
antibiotic
Bacterial
Fungal,P450 (e.g. CYP17)
Pathway
Anti-infection
Microbiology&virology
Primary Target
Miscellaneous Compounds
Indication
esophageal candidiasis, meningitis
MOA
sterol demethylase inhibitor
Therapeutic Class
Antifungal Agents
Source data