Strong action is shown by voriconazole against S. Apiospermum and C. neoformans, with 0.125-0.25 μg/mL and 0.5 μg/mL, respectively, as MICs[1]. The cytochrome P450 (CYP)-dependent enzyme 14-alpha-sterol demethylase is inhibited by voriconazole, which damages cell membranes and stops the growth of fungi [2].

In a dose-dependent manner, voriconazole (5–20 mg/kg; orally for 21 days) extends survival. In the lungs, voriconazole (40 mg/kg/day) reduces the amount of fungal growth [3].

Animal/Disease Models: Male specific-pathogen-free BALB/cByJ mice[3]
Doses: 1, 5, 20 mg/kg/day
Route of Administration: Po one time/day for 21 days
Experimental Results: Improved survival in a dose-response fashion, with median survival times (MSTs) of 21, 28, and 35 days with doses of 1, 5, and 20 mg/kg, respectively.

Absorption, Distribution and Excretion
The oral bioavailability is estimated to be 96% in healthy adults. Population pharmacokinetic studies report a reduced bioavailability pediatric patients with a mean of 61.8% (range 44.6–64.5%) thought to be due to differences in first-pass metabolism or due to differences in diet. Of note, transplant patients also have reduced bioavailability but this is known to increase with time after transplantation and may be due in part to gastrointestinal upset from surgery and some transplant medications. Tmax is 1-2 hours with oral administration. When administered with a high-fat meal Cmax decreases by 34% and AUC by 24%. pH does not have an effect on absorption of voriconazole. Differences in Cmax and AUC have been observed between healthy adult males and females with Cmax increasing by 83% and AUC by 113% although this has not been observed to significantly impact medication safety profiles.
Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.
The estimated volume of distribution of voriconazole is 4.6 L/kg. Population pharmacokinetic studies estimate the median volume of distribution to be 77.6 L with the central compartment estimated at 1.07 L/kg Voriconazole is known to achieve therapeutic concentrations in many tissues including the brain, lungs, liver, spleen, kidneys, and heart.
The clearance of voriconazole is estimated to be a mean of 5.25-7 L/h in healthy adults for the linear portion of the drug's kinetics.

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Metabolism / Metabolites
Voriconazole undergoes extensive hepatic metabolism through cytochrome enzymes CYP2C9, CYP2C19, and CYP3A4. CYP2C19 mediates N-oxidation with an apparent Km of 14 μM and an apparent Vmax of 0.22 nmol/min/nmol CYP2C19. Voriconazole N-oxide is the major circulating metabolite, accounting for 72% of radiolabeled metabolites found. CYP3A4 contributes to N-oxidation with a Km of 16 μM and Vmax of 0.05 nmol/min/nmol CYP3A4 as well as 4-hydroxylation with a Km of 11 μM and a Vmax of 0.10 nmol/min/nmol CYP3A4. CYP3A5 and CYP3A7 provide minor contributions to N-oxidation and 4-hydroxylation. The N-oxide and 4-hydroxylated metabolites undergo glucuronidation and are excreted through the urine with other minor glucuronidated metabolites.
Voriconazole has known human metabolites that include Voriconazole N-Oxide and Hydroxymethyl Voriconazole.

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Biological Half-Life
Voriconazole follows non-linear kinetics and has a terminal half-life of elimination which is dose-dependent.

Hepatotoxicity
Transient elevations in serum aminotransferase levels occur in 11% to 19% of patients on voriconazole. These elevations are usually asymptomatic and self-limited, but approximately 1% of patients require discontinuation of voriconazole because of ALT elevations. Clinically apparent hepatotoxicity is uncommon, but may be more frequent than with fluconazole and itraconazole. The injury arises within the first month of therapy and the pattern of serum enzyme elevations has been variable from cholestatic to hepatocellular. Several cases of acute liver failure attributed to voriconazole have been reported. Immunoallergic features and autoantibodies are uncommon. Recovery upon stopping therapy generally takes 6 to 10 weeks but, in some cases, the time to complete resolution may be prolonged.
Likelihood score: B (likely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of voriconazole during breastfeeding. If voriconazole is required by the mother, it is not a reason to discontinue breastfeeding. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Voriconazole is 58% bound to plasma proteins.

[1]. Voriconazole: the newest triazole antifungal agent.Proc (Bayl Univ Med Cent). 2003 Apr;16(2):241-8.

Pharmacodynamics
Voriconazole is a fungistatic triazole antifungal used to treat infections by inhibiting fungal growth. It is known to cause hepatotoxic and photosensitivity reactions in some patients.

C16H14F3N5O

349.31

349.115

137234-62-9

Voriconazole-d3;1217661-14-7;Voriconazole camphorsulfonate;137234-71-0

71616

White to off-white solid powder

1.4±0.1 g/cm3

508.6±60.0 °C at 760 mmHg

127-130°C

261.4±32.9 °C

0.0±1.4 mmHg at 25°C

1.617

0.93

1

8

5

25

448

2

C[C@@H](C1=NC=NC=C1F)[C@](CN2C=NC=N2)(C3=C(C=C(C=C3)F)F)O

BCEHBSKCWLPMDN-MGPLVRAMSA-N

InChI=1S/C16H14F3N5O/c1-10(15-14(19)5-20-7-22-15)16(25,6-24-9-21-8-23-24)12-3-2-11(17)4-13(12)18/h2-5,7-10,25H,6H2,1H3/t10-,16+/m0/s1

(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

UK-109496; UK 109496; Voriconazole; UK109496; UK109,496; UK-109,496; UK 109,496; Vfend

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 (7.16 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 (7.16 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 (7.16 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: 30% PEG400+0.5% Tween80+5% propylene glycol: 10mg/mL

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