H₁ Receptor

Fexofenadine (1-100 µM; 1 h) dose-dependently inhibits the expression of IL-6 protein in nasal fibroblasts[2].
Fexofenadine (1-100 µM; 1 h) inhibits the activation of phosphorylated p38 in nasal fibroblasts induced by histamine, but has no effect on pERK or pJNK[2].

Fexofenadine hydrochloride (oral administration; 5–20 mg/kg; once daily; 3 w) suppresses both eosinophilia and systemic anaphylaxis in C57BL/6 mice infected with T. spiralis.

Cell Line: Nasal fibroblasts
Concentration: 100 μM
Incubation Time: 1 hour
Result: Blocked pp38 activation in histamine-induced nasal fibroblasts, showed histamine-induced IL-6 production mediated by the p38 pathway.

C57BL/6 mice infected with Trichinella spiralis
5, 10 and 20 mg/kg
Oral administration; 5, 10 and 20 mg/kg; once daily; 3 weeks

Absorption, Distribution and Excretion
Fexofenadine is rapidly absorbed following oral administration and its absolute bioavailability is approximately 33%. The Tmax following oral administration is approximately 1-3 hours. The steady-state AUCss(0-12h) and Cmax following twice daily dosing of 60mg are 1367 ng/mL.h and 299 ng/mL, respectively. Fexofenadine AUC is decreased by >20% when coadministered with fruit juices (e.g. apple, orange, grapefruit) due to their inhibition of OATP transporters - for this reason, prescribing information recommends administering fexofenadine only with water. Similarly, coadministration of fexofenadine with a high-fat meal appears to decrease AUC and Cmax by >20%.
Approximately 80% of an ingested dose is eliminated in the feces, likely largely unchanged due to fexofenadine's limited metabolism, and 11% is eliminated in the urine. The principal pathways of fexofenadine elimination are biliary and renal.
The volume of distribution is approximately 5.4-5.8 L/kg.
The oral clearance of fexofenadine is approximately 50.6 L/h and the renal clearance is approximately 4.32 L/h.
Fexofenadine hydrochloride is rapidly absorbed from the GI tract following oral administration. Following oral administration of two 60-mg fexofenadine hydrochloride capsules, peak plasma concentrations are achieved in about 2.6 hours. Following oral administration of a single 60-mg capsule or 60- or 180-mg conventional tablet in healthy individuals, mean peak plasma concentrations were 131, 142, and 494 ng/mL, respectively. In healthy men, peak plasma concentrations of 167 ng/mL were achieved within 1.42 hours following oral administration of 60-mg fexofenadine hydrochloride doses every 12 hours for 9 doses.
Following oral administration of fexofenadine hydrochloride capsules in fasting children (mean age: 8-11.6 years) with a history of allergic rhinitis with or without mild asthma, peak plasma fexofenadine concentrations of about 178 or 286 ng/mL were attained in approximately 2.4 hours after a 30- or 60-mg dose, respectively.
Following oral administration of a 60-mg dose of fexofenadine hydrochloride, the AUC was 56% greater in children 7-12 years of age with allergic rhinitis than in healthy adults. Plasma exposure in children receiving 30 mg of fexofenadine hydrochloride is similar to that of adults receiving 60 mg of the drug. Limited data indicate that peak plasma fexofenadine concentrations in adolescents (12-16 years of age) were similar to those in adults, while peak plasma concentrations in geriatric adults (65 years of age and older) were 99% greater than in healthy individuals younger than 65 years of age. AUC also was higher in geriatric adults (65-80 years of age) than in younger adults (19-45 years of age)...
Peak plasma concentrations of fexofenadine were 87 and 111% higher in patients with mild (creatinine clearance of 41-80 mL/minute) to severe (creatinine clearance of 11-40 mL/minute) renal impairment, respectively, compared with those observed in healthy adults. In patients undergoing dialysis (creatinine clearance of 10 mL/minute or less), peak plasma concentrations of fexofenadine were 82% higher than in healthy adults.
For more Absorption, Distribution and Excretion (Complete) data for FEXOFENADINE (12 total), please visit the HSDB record page.

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Metabolism / Metabolites
Fexofenadine is very minimally metabolized, with only 5% of an ingested dose undergoing hepatic metabolism. The only identified metabolites are a methyl ester of fexofenadine (3.6% of the total dose) and MDL 4829 (1.5% of the total dose). The enzymes responsible for this metabolism have not been elucidated.
About 5% of a single oral dose of fexofenadine is metabolized.
Negligible amounts of fexofenadine (about 0.5-1.5% of a dose) are metabolized in the liver by the cytochrome P-450 microsomal enzyme system to an inactive metabolite, while about 3.5% of a fexofenadine dose is metabolized by a second metabolic pathway (unrelated to the cytochrome P-450 microsomal enzyme system) to the methyl ester derivative of fexofenadine. The methyl ester metabolite of fexofenadine is found only in feces, and it has been suggested that the intestinal flora probably are involved in this metabolism.
Approximately 5% of the total dose is metabolized, by cytochrome P450 3A4 and by intestinal microflora.
Half Life: 14.4 hours

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Biological Half-Life
The terminal elimination half-life is approximately 11-15 hours.
Following oral administration of 60 mg of fexofenadine hydrochloride twice daily in healthy individuals, the mean elimination half-life of the drug at steady state reportedly is about 14.4-14.6 hours; mean elimination half-life reportedly was similar in geriatric adults (65 years of age or older) who received a single 80-mg oral dose of fexofenadine hydrochloride.
... Elimination half-life was about 18 hours in fasting children (mean age: 8-11.6 years) who received single oral 30- or 60-mg doses of fexofenadine hydrochloride as capsules.
In patients with mild (creatinine clearance of 41-80 mL/minute) to severe (creatinine clearance of 11-40 mL/minute) renal impairment, mean elimination half-lives were 59 and 72% longer than those observed in healthy individuals, respectively.
In patients undergoing dialysis (creatinine clearance of 10 mL/minute or less), elimination half-life was 31% longer than in healthy individuals.

Toxicity Summary
Like other H1-blockers, Fexofenadine competes with free histamine for binding at H1-receptors in the GI tract, large blood vessels, and bronchial smooth muscle. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms (eg. nasal congestion, watery eyes) brought on by histamine. Fexofenadine exhibits no anticholinergic, antidopaminergic, alpha1-adrenergic or beta-adrenergic-receptor blocking effects.

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Interactions
Increased concentrations of fexofenadine have been reported in 2 controlled drug interaction studies in healthy individuals receiving 120 mg of fexofenadine hydrochloride twice daily concomitantly with erythromycin dosages of 500 mg every 8 hours or ketoconazole 400 mg once daily. In these studies, area under the plasma-concentration time curve (AUC) of fexofenadine increased by 109 or 164% following concomitant administration with erythromycin or ketoconazole, respectively, while peak plasma concentrations of fexofenadine increased by 82 or 135%, respectively. However, no clinically important adverse effects or changes in the QT interval corrected for rate (QTc) were reported after concomitant administration of erythromycin or ketoconazole with fexofenadine.
Administration of a single 120-mg dose (2 capsules of 60 mg) of fexofenadine hydrochloride within 15 minutes of administration of an aluminum and magnesium hydroxides antacid (Maalox) decreased the AUC and peak plasma concentration of fexofenadine by 41 and 43%, respectively. Therefore, the manufacturer states that fexofenadine (alone or in fixed combination with pseudoephedrine hydrochloride) should not be taken closely in time with antacids containing aluminum and magnesium.
Fruit (grapefruit, orange, apple) juices may reduce bioavailability and systemic exposure of fexofenadine. In clinical studies, the size of wheal and flare was substantially larger when fexofenadine hydrochloride was administered with grapefruit juice or orange juice compared with water; based on literature reports, the same effects may be extrapolated to other fruit juices such as apple juice. The clinical importance of these observations is unknown. Based on a population pharmacokinetic analysis of combined data from the studies using concomitant grapefruit juice or orange juice with data from a bioequivalence study, bioavailability of fexofenadine was reduced by 36%. Therefore, to maximize the effects of fexofenadine, the manufacturer recommends that the drug be administered with water.

[1]. The effects of fexofenadine on eosinophilia and systemic anaphylaxis in mice infected with Trichinella spiralis. Int Immunopharmacol. 2004 Mar;4(3):367-75.

[2]. Histamine Promotes the Release of Interleukin-6 via the H1R/p38 and NF-κB Pathways in Nasal Fibroblasts. Allergy Asthma Immunol Res. 2014 Nov;6(6):567-72.

[3]. Vectorial transport of fexofenadine across Caco-2 cells: involvement of apical uptake and basolateral efflux transporters. Mol Pharm. 2011 Oct 3;8(5):1677-86.

Therapeutic Uses
Histamine H1 antagonists
Antihistaminic
Fexofenadine is indicated to relieve symptoms that are associated with seasonal allergic rhinitis, such as sneezing;rhinorrhea; itchy eyes, nose and throt; and red watery eyes. /Included in US product label/
Fexofenadine is indicated for the treatment of uncomplicated skin manifestations of chronic idiopathic urticaria. It significantly reduces pruritus and the number of wheals. /Included in US product label/

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Drug Warnings
In controlled clinical studies in patients 12 years of age and older with allergic rhinitis receiving oral fexofenadine hydrochloride dosages of 60 mg twice daily or placebo, drowsiness or fatigue occurred in 1.3% of patients, compared with 0.9% of those receiving placebo. In these studies in patients receiving fexofenadine hydrochloride dosages of 180 mg once daily (as conventional tablets) or placebo, headache was reported in 10.6 or 7.5% of patients, respectively. In controlled studies in children 6-11 years of age with seasonal allergic rhinitis receiving fexofenadine hydrochloride dosages of 30 mg twice daily or placebo, headache was reported in 7.2 or 6.6% of patients, respectively, while pain was reported in 2.4 or 0.4% of patients, respectively.
Sleep disorder, insomnia, or paroniria has occurred in patients receiving fexofenadine hydrochloride.
During controlled clinical studies, nausea and dyspepsia were reported in 1.6 and 1.3%, respectively, of patients receiving oral fexofenadine hydrochloride dosages of 60 mg twice daily versus 1.5 and 0.6%, respectively, of those receiving placebo.
Clinical data from over 2000 patients indicate that fexofenadine hydrochloride lacks the cardiotoxic potential of its parent drug terfenadine. In 714 patients with seasonal allergic rhinitis, fexofenadine hydrochloride dosages of 60-240 mg twice daily were not associated with statistically significant mean increases in the QT interval corrected for rate (QTc) in controlled clinical studies. In addition, in 231 healthy individuals, fexofenadine hydrochloride dosages of 240 mg given once daily for 1 year also were not associated with statistically significant increases in the mean QTc. Even at dosages exceeding these (e.g., up to 400 mg twice daily for 6 days in 40 patients, up to 690 mg twice daily for about 1 month in 32 patients, up to 800 mg given in a single dose in 87 patients), statistically significant mean increases in the QTc or other ECG abnormalities have not been reported in healthy adults or patients with seasonal allergic rhinitis.
For more Drug Warnings (Complete) data for FEXOFENADINE (15 total), please visit the HSDB record page.

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Pharmacodynamics
Fexofenadine relieves allergy symptoms by antagonizing the actions of histamine, an endogenous compound predominantly responsible for allergic symptomatology. The relatively long duration of action of fexofenadine (approximately 24 hours) allows for once or twice daily dosing, and its rapid absorption allows for an onset of action within 1-3 hours. Fexofenadine should not be taken with fruit juice, as this may impair its absorption.

C32H39NO4

501.65636

501.287

C, 76.61; H, 7.84; N, 2.79; O, 12.76

83799-24-0

Fexofenadine hydrochloride; 153439-40-8; Fexofenadine-d6; 548783-71-7; Fexofenadine-d6 Methyl Ester; 1286458-00-1; Fexofenadine-d3; Fexofenadine-d10; 1215900-18-7

3348

Off-white to light yellow solid powder

1.2±0.1 g/cm3

697.3±55.0 °C at 760 mmHg

218-220ºC

375.5±31.5 °C

0.0±2.3 mmHg at 25°C

1.597

4.8

3

5

10

37

678

0

O=C(C(C)(C)C1C=CC(C(CCCN2CCC(C(C3C=CC=CC=3)(C3C=CC=CC=3)O)CC2)O)=CC=1)O

RWTNPBWLLIMQHL-UHFFFAOYSA-N

InChI=1S/C32H39NO4/c1-31(2,30(35)36)25-17-15-24(16-18-25)29(34)14-9-21-33-22-19-28(20-23-33)32(37,26-10-5-3-6-11-26)27-12-7-4-8-13-27/h3-8,10-13,15-18,28-29,34,37H,9,14,19-23H2,1-2H3,(H,35,36)

2-[4-[1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]piperidin-1-yl]butyl]phenyl]-2-methylpropanoic acid

Telfast; Fexofenadine; Allegra; Carboxyterfenadine; MDL 16.455

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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.)