IL-17 mRNA is strongly inhibited by Enilconodium sulfate (Enilconodium; 3, 10, 30 μM; 6 hours duration)[1]. RT-PCR of sulfate expression exclusively in mPXR using imazalil (1, 3, 10, 30, 100 μM) over 24 hours [1].

Imazalil (enconazole; 25-100 mg/kg; intraperitoneal) sulfate dramatically raises cardiac Cyp3a11 mRNA levels in a dosed manner [2]. Imazalil (75 mg/kg; i.p.; twice; one daily) sulfate coupled with TCPOBOP (3 mg/kg) significantly raised the number of Ki-67 positive nuclei and Mcm2 mRNA compared with treatment alone level. Imazalil sulfate can increase TCPOBOP treatment-mediated liver cell proliferation [2]. (0.1, 0.5, 2.5 mg/kg; in floods; for 15 weeks) Sulfate induces oxidation termination and bile acid action in camels C57BL/6 camels [3].

RT-PCR[1]
Cell Types: EL4 cells
Tested Concentrations: 3, 10, 30 μM
Incubation Duration: 6 h
Experimental Results: Significant inhibition of IL-17 mRNA. Reporter gene expression is induced dose-dependently in HepG2 cells [2].

Animal/Disease Models: IMZ Male C57BL/6N mice [2]
Doses: 25, 50, 75, 100 mg/kg
Route of Administration: intraperitoneal (ip) injection; single dose
Experimental Results: Dramatically increased liver Cyp3a11 mRNA levels in a dose-dependent manner.

Absorption, Distribution and Excretion
Comparison of the excretion patterns after oral and intravenous dosing suggests that the bioavailability, and therefore the absorption, of imazalil given orally is high.
Imazalil technical (purity = 98.7%) and 14C-imazalil (117.1 uCi/mL; purity = 99.9%) was administered to 4 groups of 6-8 Wistar rats. Group A: 5 rats/sex & reserve group I (1/sex) were injected in tail vein with 1.25 mg 14C-imazalil/kg (single dose). Group B: 5/sex were dosed by gastric intubation at 1.25 mg 14C-imazalil/kg (single dose). Group C: 5/sex & reserve group K (3/sex) were dosed by gastric intubation at 1.25 mg imazalil/kg/day for 14 days. At 24 hours after the last unlabelled dose, 5/sex received a single oral dose of 14C-imazalil at 1.25 mg/kg. Group D: 5/sex & reserve group L (1/sex) were dosed by gastric intubation at 20 mg 14C imazalil/kg (single dose). At 96 hours post-dosing (Groups B, C & D) were sacrificed for tissue collection. Group A & reserve rats (those not used) were sacrificed & disposed of. Distribution showed that after 96 hrs only 1% of 14C-imazalil was recovered in tissues and carcass. There was a dose-response in tissue levels of compound but there was no accumulation after multiple dosing. There were no sex differences. Approximately 50% of tissue 14C-imazalil was recovered in liver 96 hrs after gavage, levels in liver were approximately 20 times higher and kidney, lung and adrenals 4-10 times higher than corresponding blood levels. All other tissues examined had concentrations of 14C-imazalil < that of blood, with none detected in brain. By all routes and methods of administration, the majority (approximately 90%) of radioactivity was excreted within 24 hrs (primarily in urine & slightly higher in females).
A striking decrease was found in the effectiveness of thiabendazole (TBZ), benomyl, imazalil and prochloraz in controlling blue and green molds as a result of delaying the fungicidal treatments. Although imazalil and prochloraz gave low protective activity, they had high antisporulation efficiency. On the other hand, thiabendazole and benomyl protected fruits against subsequent infection. Storage was found to have a pronounced effect on the residual activity of imazalil compared with thiabendazole. Residues of imazalil and thiabendazole were found in orange jam made from fungicide-treated fruits.
Imazalil is absorbed, distributed, and metabolized rapidly in rodent species. It is a sulfate, of which approximately 90% is excreted within 96 hours.

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Metabolism / Metabolites
... Little imazalil was excreted unchanged /in rats/: less than 1% of the administered dose in the feces and trace amounts in the urine. The compound was metabolized to at least 25 metabolites. Three major metabolites were identified, (+/-)-1-[2-(2,4-dichlorophenyl)-2-(2,3-dihydroxypropyloxy)ethyl]-imidaxolidine-2,5-dione (metabolite 8), (+/-)-1-[2-(2,4-dichlorophenyl)-2-(2,3-dihydroxypropyloxy)ethyl]-1H-imidazole (metabolite 10), and (+/-)-1-(2,4-dichlorophenyl)-2-imidazol-1-ylethanol (metabolite 11). The main routes of metabolism were epoxidation, epoxide hydratation, oxidative O-dealkylation, oxidation, and scission and oxidative N-dealkylation. The metabolic pattern was similar after oral and intravenous administration and in animals of each sex.

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Biological Half-Life
The half-time was about 2 hrs /in humans/.

Toxicity Data
LC50 (rat) = 16,000 mg/m3/4h

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Non-Human Toxicity Values
LD50 Rat oral 227 mg/kg
LD50 Dog oral greater than 640 mg/kg
LC50 Rat inhalation 16 g/ cu m/4 hr
LD50 Rat skin 4200 mg/kg
LD50 Rat ip 155 mg/kg

[1]. Hiroyuki Kojima, et al. Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):338-45.
[2]. Shohei Yoshimaru, et al. Acceleration of murine hepatocyte proliferation by imazalil through the activation of nuclear receptor PXR. J Toxicol Sci. 2018;43(7):443-450.
[3]. Cuiyuan Jin, et al. Chronic exposure of mice to low doses of imazalil induces hepatotoxicity at the physiological, biochemical, and transcriptomic levels. Environ Toxicol. 2018 Jun;33(6):650-658.

Imazalil is a slightly yellow to brown solidified oil. Non-corrosive. Used as a fungicide.

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Mechanism of Action
Two single-copy genes, designated atrA and atrB (ATP-binding cassette transporter A and B), were cloned from the filamentous fungus Aspergillus nidulans and sequenced. Based on the presence of conserved motifs and on hydropathy analysis, the products encoded by atrA and atrB can be regarded as novel members of the ATP-binding cassette (ABC) superfamily of membrane transporters. Both products share the same topology as the ABC transporters PDR5 and SNQ2 from Saccharomyces cerevisiae and CDR1 from Candida albicans, which are involved in multidrug resistance of these yeasts. Significant homology also occurs between the ATP-binding cassettes of atrA and atrB, and those of mammalian ABC transporters (P-glycoproteins). The transcription of atrA and, i particular, atrB in mycelium of A. nidulans is strongly enhanced by treatment with several drugs, including antibiotics, azole fungicides and plant defense toxins. The enhanced transcription is detectable within a few minutes after drug treatment and coincides with the beginning of energy-dependent drug efflux activity, reported previously in the fungus for azole fungicides. Transcription of the atr genes has been studied in a wild-type and in a series of isogenic strains carrying the imaA and/or imaB genes, which confer multidrug resistance to various toxic compounds such as the azole fungicide imazalil. atrB is constitutively transcribed at a low level in the wild-type and in strains carrying imaA or imaB. Imazalil treatment enhances transcription of atrB to a similar extent in all strains tested. atrA, unlike atrB, displays a relatively high level of constitutive expression in mutants carrying imaB. Imazalil enhances transcription of atrA more strongly in imaB mutants, suggesting that the imaB locus regulates atrA. Functional analysis demonstrated that cDNA of atrB can complement the drug hypersensitivity associated with DPR5 deficiency in S. cerevisiae.

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Therapeutic Uses
Mesh Heading: fungicides, industrial
MEDICATION (VET): Antifungal
... Used in the therapy of human alternariosis, an uncommon infection.

C14H16CL2N2O5S

395.26

360.01

58594-72-2

Imazalil-d5 sulfate;1398065-92-3

173636

Slightly yellow to brown crystalline mass.
Solidified oil
Brownish oil

1.23g/cm3

448.5ºC at 760mmHg

52.7ºC

225.1ºC

4.561

2

6

6

24

372

0

C=CCOC(CN1C=CN=C1)C2=C(C=C(C=C2)Cl)Cl.OS(=O)(=O)O

XVTXMTOYQVRHSK-UHFFFAOYSA-N

InChI=1S/C14H14Cl2N2O.H2O4S/c1-2-7-19-14(9-18-6-5-17-10-18)12-4-3-11(15)8-13(12)16;1-5(2,3)4/h2-6,8,10,14H,1,7,9H2;(H2,1,2,3,4)

1-[2-(2,4-dichlorophenyl)-2-prop-2-enoxyethyl]imidazole;sulfuric acid

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)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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