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Drug

D0417 | Fluconazole

Molecular Formula C13H12F2N6O
Molecular Weight 306.27
Structure
State solid
Clearance This drug is mainly eliminated by the kidneys and the mean body clearance in adults is reported to be 0.23 mL/min/kg.[FDA label] 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).[A178792] Clearance in the pediatric population varies according to age, as does clearance in patients with renal failure.[FDA label]
Volume of distribution The apparent volume of distribution is said to be similar to the volume of distribution of total body water.[FDA label] One clinical study of healthy volunteers administered 50 mg/kg of fluconazole was 39L, based on a body weight of 60kg.[A178792] 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.[A178792,FDA label] 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.[L6496] Saliva and sputum concentrations of fluconazole are found to be similar to the plasma concentrations.[L6505] 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[L6496]. The meninges are increasingly permeable to fluconazole in states of inflammation, facilitating treatment in meningitis.[A178801]
Route of elimination 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]
Protein binding The protein binding of fluconazole is low and estimated to be 11 to 12%.[FDA label,A178792]
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]
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]
Trade names Diflucan
Description azole antifungal

D

J

J02AC01 Fluconazole


[J02AC] Triazole derivatives


[J02A] ANTIMYCOTICS FOR SYSTEMIC USE


[J02] ANTIMYCOTICS FOR SYSTEMIC USE


[J] Antiinfectives for systemic use

J01RA07 Azithromycin, fluconazole and secnidazole


[J01RA] Combinations of antibacterials


[J01R] COMBINATIONS OF ANTIBACTERIALS


[J01] ANTIBACTERIALS FOR SYSTEMIC USE


[J] Antiinfectives for systemic use

D01AC15 Fluconazole


[D01AC] Imidazole and triazole derivatives


[D01A] ANTIFUNGALS FOR TOPICAL USE


[D01] ANTIFUNGALS FOR DERMATOLOGICAL USE


[D] Dermatological drugs

Toxicity Dose Time Species Model Method Action Positive criterion Reference
MEMBRANE POTENTIAL 512.7 µM 30 mins mouse liver mitochondria Rh123 fluorescence (excitation 485 nm, emission 535 nm) are recorded using a fluorescence multi-well plate reader (mCICCP (20 µM) treatments was considered as the 100% baseline for ΔΨm loss) decrease EC20 36
RESPIRATION > 400 µM 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Rotenone (2µM) was used as 100% baseline for complex I inhibition. decrease EC20 36
RESPIRATION 186.6 µM 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Oligomycin A (1µM) was used as 100% baseline for complex II inhibition. decrease EC20 36
STATE 3 RESPIRATION rat liver mitochondria Clark electrode Negative 303
ELECTRON TRANSPORT CHAIN 50 μM bovine heart mitochondria Measurement of complex I activity Negative p < 0.05 3
ELECTRON TRANSPORT CHAIN 50 μM bovine heart mitochondria Measurement of complex II + III activity Negative p < 0.05 3
ELECTRON TRANSPORT CHAIN 50 μM bovine heart mitochondria Measurement of complex II + III activity Negative p < 0.05 3
ELECTRON TRANSPORT CHAIN 50 μM bovine heart mitochondria Measurement of complex IV activity Negative p < 0.05 3
ELECTRON TRANSPORT CHAIN 50 μM bovine heart mitochondria Measurement of complex V activity Negative p < 0.05 3
SWELLING > 400 µM 30 mins mouse liver mitochondria swelling assay: Absorbance at 545 nm using a fluorescence multi-well plate reader (CaCl2 (50 µM) was considered as the 100% baseline for the swelling ) increase EC20 36

Target Dose Time Species Model Method Action Positive criterion Reference
NADH:ubiquinone reductase 50 μM bovine heart mitochondria Measurement of complex I activity Negative p < 0.05 3
NADH:ubiquinone reductase > 400 µM 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Rotenone (2µM) was used as 100% baseline for complex I inhibition. inhibit EC20 36
Succinate dehydrogenase 50 μM bovine heart mitochondria Measurement of complex II + III activity Negative p < 0.05 3
Succinate dehydrogenase 186.6 µM 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Oligomycin A (1µM) was used as 100% baseline for complex II inhibition. inhibit EC20 36
Quinol--cytochrome-c reductase 50 μM bovine heart mitochondria Measurement of complex II + III activity Negative p < 0.05 3
Cytochrome c oxidase 50 μM bovine heart mitochondria Measurement of complex IV activity Negative p < 0.05 3
ATP synthase 50 μM bovine heart mitochondria Measurement of complex V activity Negative p < 0.05 3
Cytochrome c > 400 µM 30 mins mouse liver mitochondria Cytochrome c release was evaluated using ELISA kit ( 20 µg/ml Alamethicin was used as 100% baseline) release EC20 36

Pictogram Signal Statements Precautionary Statement Codes
Danger

Aggregated GHS information provided by 294 companies from 27 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.


Reported as not meeting GHS hazard criteria by 1 of 294 companies. For more detailed information, please visit ECHA C&L website


Of the 26 notification(s) provided by 293 of 294 companies with hazard statement code(s):


H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]


H315 (79.52%): Causes skin irritation [Warning Skin corrosion/irritation]


H319 (72.35%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]


H335 (18.43%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure


Respiratory tract irritation]


H360 (70.65%): May damage fertility or the unborn child [Danger Reproductive toxicity]


H362 (13.99%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]


H371 (55.63%): May cause damage to organs [Warning Specific target organ toxicity, single exposure]


H372 (52.56%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]


H412 (12.97%): Harmful to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]


Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.


 P201, P202, P260, P261, P263, P264, P270, P271, P273, P280, P281, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P309+P311, P312, P314, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501; (The corresponding statement to each P-code can be found at the GHS Classification page.)

Organism Test type Route Dose (normalized dose) Effect Source
man TDLo oral 60mg/kg/3W-I (60mg/kg) Postgraduate Medical Journal. Vol. 67, Pg. 1084, 1991.
rat LD50 unreported > 1gm/kg (1000mg/kg) Antimicrobial Agents and Chemotherapy. Vol. 29, Pg. 161, 1986.
rat LD50 intravenous > 200mg/kg (200mg/kg) Drugs in Japan Vol. -, Pg. 983, 1990.
rat LD50 intraperitoneal > 941mg/kg (941mg/kg) Drugs in Japan Vol. -, Pg. 983, 1990.
rat LD50 oral 1271mg/kg (1271mg/kg) Drugs in Japan Vol. -, Pg. 983, 1990.
dog LD50 oral > 300mg/kg (300mg/kg) Drugs in Japan Vol. -, Pg. 983, 1990.
man TDLo oral 1040mg/kg/26W (1040mg/kg) skin and appendages (skin): hair: other Annals of Internal Medicine. Vol. 123, Pg. 354, 1995.
dog LD50 intravenous > 100mg/kg (100mg/kg) Drugs in Japan Vol. -, Pg. 983, 1990.
mouse LD50 oral 1408mg/kg (1408mg/kg) Drugs in Japan Vol. -, Pg. 983, 1990.
women TDLo oral 1456mg/kg/26W (1456mg/kg) skin and appendages (skin): hair: other Annals of Internal Medicine. Vol. 123, Pg. 354, 1995.
mouse LD50 unreported > 1gm/kg (1000mg/kg) Antimicrobial Agents and Chemotherapy. Vol. 29, Pg. 161, 1986.
women TDLo multiple routes 426mg/kg/37D- (426mg/kg) Annals of Internal Medicine. Vol. 131, Pg. 797, 1999.
mouse LD50 intravenous > 200mg/kg (200mg/kg) Drugs in Japan Vol. -, Pg. 983, 1990.
mouse LD50 intraperitoneal 1273mg/kg (1273mg/kg) Drugs in Japan Vol. -, Pg. 983, 1990.


  • .alpha.-(2,4-Difluorophenyl)-.alpha.-(1H-1,2,4-triazol-1-ylmethyl)-1H-1,2,4-triazole-1-ethanol 1,2,4-triazol-1-yl)propan-2-ol 1-p-tolylpyridin-2(1H)-one
    123631-92-5 1H-1,2,4-Triazole-1-ethanol, alpha-(2,4-difluorophenyl)-alpha-(1H-1,2,4-triazol-1-ylmethyl)- 2,4-Difluoro-alpha,alpha-1-bis(1H-1,2,4-triazol-1-ylmethyl)benzyl alcohol
    2,4-Difluoro-alpha,alpha-bis(1H-1,2,4-triazol-1-ylmethyl)benzyl alcohol 2-(2,4-DIFLUOROPHENYL)-1,3-DI(1H-1,2,4-TRIAZOL-1-YL)PROPAN-2-OL 2-(2,4-Difluoro-phenyl)-1,3-bis-[1,2,4]triazol-1-yl-propan-2-ol
    2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-Difluorophenyl)-1,3-di-1H-1,2,4-triazol-1-ylpropan-2-ol
    2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)-2-propanol 2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-difluorophenyl)-1,3-di(1,2,4-triazolyl)propan-2-ol
    2-(2,4-difluorophenyl)-1,3-di(1H- 2-[2,4-bis(fluoranyl)phenyl]-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol 340962-81-4
    386F734 86386-73-4 86386-73-4,155347-36-7(H2O),159532-41-9(methanesulfonate)
    8VZV102JFY A841625 AB00052399-07
    AB00052399-08 AB00052399_09 AB00052399_10
    AB0008515 AB1010904 ABP001077
    AC-428 AKOS000280854 ALPHA-(2,4-DIFLUOROPHENYL)-ALPHA-(1H-1,2,4-TRIAZOLE-1-YLMETHYL)-1H-1,2,4-TRIAZOLE-1-ETHANOL
    ANW-42860 Alflucoz BBL005614
    BCP28522 BDBM25817 BIDD:GT0799
    BIOZOLENE BRD-K05977355-001-02-6 BRD-K05977355-001-09-1
    BSPBio_003504 Baten Biocanol
    Biozolene C07002 C13H12F2N6O
    CAS-86386-73-4 CCG-39065 CCRIS 7211
    CF0055 CHEBI:46081 CHEMBL106
    CPD000471882 CS-1835 CTK4B3573
    Canzol Certified Reference Material Cryptal
    D00322 DB00196 DIFLUCAN IN DEXTROSE 5% IN PLASTIC CONTAINER
    DIFLUCAN IN SODIUM CHLORIDE 0.9% DIFLUCAN IN SODIUM CHLORIDE 0.9% IN PLASTIC CONTAINER DL-407
    DRG-0005 DSSTox_CID_627 DSSTox_GSID_20627
    DSSTox_RID_75701 DTXSID3020627 Diflazon
    Diflucan Diflucan (TN) Dimycon
    DivK1c_001030 ELAZOR EN300-53634
    Elazor F0677 F2173-0496
    FLC FLCZ FLUCONAZOLE
    FT-0626437 Flucazol Fluconazol
    Fluconazol [Spanish] Fluconazole & Human recombinant granulocyte colony stimulating factor Fluconazole & MC-510,011
    Fluconazole & hGCSF Fluconazole (JP17/USAN/INN) Fluconazole (f)
    Fluconazole 2.0 mg/ml in Methanol Fluconazole [USAN:INN:BAN:JAN] Fluconazole [USAN:USP:INN:BAN:JAN]
    Fluconazole [USAN] Fluconazole for peak identification, European Pharmacopoeia (EP) Reference Standard Fluconazole in combination with MGCD290
    Fluconazole in dextrose 5% in plastic container Fluconazole in sodium chloride 0.9% Fluconazole in sodium chloride 0.9% in plastic container
    Fluconazole solution, 2.0 mg/mL in methanol, ampule of 1 mL, certified reference material Fluconazole, 98% Fluconazole, >=98% (HPLC), powder
    Fluconazole, European Pharmacopoeia (EP) Reference Standard Fluconazole, Pharmaceutical Secondary Standard Fluconazole, United States Pharmacopeia (USP) Reference Standard
    Fluconazole,(S) Fluconazolum Fluconazolum [Latin]
    Flucoral Flucostat Flukezol
    Flunazol Flunizol Flusol
    Fluzon [Antifungal] Fluzone Forcan
    Fuconal Fungata HMS1922O10
    HMS2090I20 HMS2093M21 HMS2230O22
    HMS3259H13 HMS3373I19 HMS3654P15
    HMS3715F21 HMS3748G19 HMS503M21
    HSDB 7420 HY-B0101 IDI1_001030
    J10407 KBio1_001030 KBio2_002134
    KBio2_004702 KBio2_007270 KBio3_003009
    KBioGR_000360 KBioSS_002134 KM2402
    KS-000000NR KS-1059 LS-1858
    Loitin MCULE-8641424658 MFCD00274549
    MG-3290 and Fluconazole MGCD290 and Fluconazole MLS001066394
    MLS001165780 MLS001195645 MLS001304713
    MLS001306492 MLS006011884 Mutum
    NC00650 NCGC00095089-01 NCGC00095089-02
    NCGC00095089-04 NCGC00095089-05 NCGC00095089-06
    NCGC00095089-07 NCGC00095089-08 NCGC00095089-09
    NCGC00095089-10 NCGC00095089-11 NCGC00254412-01
    NCGC00259789-01 NINDS_001030 NSC-758661
    NSC758661 Oxifugol Pharmakon1600-01503975
    Pritenzol Q-201120 Q411478
    RFHAOTPXVQNOHP-UHFFFAOYSA-N SAM002589905 SAM002589957
    SBB066063 SBI-0051880.P002 SC-12182
    SC-26357 SC-35622 SCHEMBL3151
    SMR000471882 SPBio_001613 SPECTRUM1503975
    SR-01000765440 SR-01000765440-2 SR-01000765440-4
    SR-01000765440-8 ST51039043 STK619301
    SW199616-2 Spectrum2_001607 Spectrum3_001912
    Spectrum4_000090 Spectrum5_001277 Spectrum_001654
    Syscan TR-038046 TRIFLUCAN
    Tox21_111419 Tox21_111419_1 Tox21_202240
    Tox21_300581 Triconal Triflucan
    UK 49858 UK-049858 UK-49,858
    UK-49858 UK-49858;UK 49858;UK49858 UNII-8VZV102JFY
    Z235354561 ZINC4009 Zemyc
    Zoltec Zonal alpha-(2,4-Difluorophenyl)-alpha-(1H-1,2,4-triazol-1-ylmethyl)-1H-1,2,4-triazole-1-ethanol
    cid_3365 fluconazole s1331

    DrugBank Name Fluconazole
    DrugBank DB00196
    CAS Number 1124197-58-5, 123631-92-5, 170151-24-3, 19006-80-5, 340962-81-4, 86386-73-4
    PubChem Compound 3365
    KEGG Compound ID C07002
    KEGG Drug D00322
    ChEBI 46081
    PharmGKB PA449653
    ChemSpider 3248
    BindingDB 25817.0
    TTD DAP000628
    Wikipedia Fluconazole
    HET TPF