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 after oral administration, with an absolute bioavailability of approximately 33%. The time to peak concentration (Tmax) after oral administration is approximately 1–3 hours. With a dose of 60 mg twice daily, the steady-state AUCss (0–12 h) and Cmax are 1367 ng/mL·h and 299 ng/mL, respectively. Because fruit juices (e.g., apple, orange, grapefruit juice) inhibit the OATP transporter, co-administration with fruit juice can reduce the AUC of fexofenadine by more than 20%. Therefore, prescribing information recommends taking fexofenadine only with water. Similarly, co-administration with a high-fat meal appears to reduce AUC and Cmax by more than 20%. Approximately 80% of the ingested dose is excreted in feces, and due to the limited metabolism of fexofenadine, most of it is likely excreted unchanged; 11% is excreted in urine. The main routes of excretion for fexofenadine are bile and kidneys. 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. After oral administration, fexofenadine hydrochloride is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations are reached approximately 2.6 hours after oral administration of two 60 mg fexofenadine hydrochloride capsules. In healthy individuals, the mean peak plasma concentrations after oral administration of a single 60 mg capsule, or a 60 mg or 180 mg conventional tablet are 131, 142, and 494 ng/mL, respectively. In healthy men, an oral dose of 60 mg fexofenadine hydrochloride every 12 hours for a total of 9 doses resulted in a peak plasma concentration of 167 ng/mL within 1.42 hours. In fasting children (mean age: 8–11.6 years), regardless of whether they had mild asthma, those with a history of allergic rhinitis reached peak plasma fexofenadine concentrations of approximately 178 ng/mL or 286 ng/mL within approximately 2.4 hours after oral administration of fexofenadine hydrochloride capsules. In children aged 7–12 years with allergic rhinitis, the AUC after oral administration of 60 mg fexofenadine hydrochloride was 56% higher than in healthy adults. Plasma exposure in children after taking 30 mg fexofenadine hydrochloride was similar to that in adults taking 60 mg. Limited data suggest that peak plasma concentrations of fexofenadine in adolescents (12–16 years) were similar to those in adults, while peak plasma concentrations in older adults (65 years and older) were 99% higher than in healthy individuals under 65 years of age. The AUC in older adults (65-80 years) is also higher than in younger adults (19-45 years)...
Compared to healthy adults, patients with mild renal impairment (creatinine clearance 41-80 mL/min) and severe renal impairment (creatinine clearance 11-40 mL/min) showed 87% and 111% higher peak plasma concentrations of fexofenadine, respectively. In patients undergoing dialysis (creatinine clearance ≤10 mL/min), peak plasma concentrations of fexofenadine were 82% higher than in healthy adults.
For more complete data on the absorption, distribution, and excretion of fexofenadine (12 in total), please visit the HSDB record page.

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Metabolism/Metabolites
Fexofenadine is metabolized very little, with only 5% of the ingested dose metabolized by the liver. The only identified metabolites are fexofenadine methyl ester (3.6% of total dose) and MDL 4829 (1.5% of total dose). The enzymes responsible for this metabolism have not been elucidated. Approximately 5% of a single oral dose of fexofenadine is metabolized. A very small amount of fexofenadine (approximately 0.5-1.5% of the dose) is metabolized in the liver to inactive metabolites via the cytochrome P-450 microsomal enzyme system, while approximately 3.5% of the fexofenadine dose is metabolized to fexofenadine methyl ester derivatives via a second metabolic pathway (unrelated to the cytochrome P-450 microsomal enzyme system). Fexofenadine methyl ester metabolites are only found in feces, and studies have suggested that gut microbiota may be involved in this metabolic process. Approximately 5% of the total dose is metabolized by cytochrome P450 3A4 and gut microbiota. Half-life: 14.4 hours. The terminal elimination half-life is approximately 11-15 hours.
It has been reported that in healthy individuals, the mean elimination half-life of fexofenadine hydrochloride after twice-daily oral administration of 60 mg is approximately 14.4–14.6 hours at steady state; similar mean elimination half-life has been reported in elderly individuals (65 years and older) after a single oral administration of 80 mg fexofenadine hydrochloride.
…In fasting children (mean age: 8–11.6 years), the elimination half-life after a single oral administration of 30 mg or 60 mg fexofenadine hydrochloride capsules is approximately 18 hours.
The mean elimination half-life in patients with mild (creatinine clearance 41–80 mL/min) to severe (creatinine clearance 11–40 mL/min) renal impairment is 59% and 72% longer, respectively, than in healthy individuals.
The elimination half-life in patients undergoing dialysis (creatinine clearance ≤10 mL/min) is 31% longer than in healthy individuals.

Toxicity Summary
Like other H1 receptor blockers, fexofenadine competitively binds to H1 receptors in the gastrointestinal tract, large blood vessels, and bronchial smooth muscle with free histamine. This blocks the action of endogenous histamine, thereby temporarily relieving histamine-induced adverse reactions (e.g., nasal congestion, tearing). Fexofenadine does not have anticholinergic, antidopaminergic, α1-adrenergic, or β-adrenergic receptor blocking effects. Interactions
In two controlled drug interaction studies, increased fexofenadine concentrations were reported in healthy subjects when they were co-administered with 120 mg fexofenadine hydrochloride (twice daily) and 500 mg erythromycin (every 8 hours) or 400 mg ketoconazole (once daily). In these studies, the area under the plasma concentration-time curve (AUC) of fexofenadine increased by 109% and 164%, respectively, while the peak plasma concentration increased by 82% and 135%, respectively, when co-administered with erythromycin or ketoconazole. However, no clinically significant adverse reactions or changes in corrected QT interval (QTc) have been reported when fexofenadine is used in combination with erythromycin or ketoconazole. A single dose of 120 mg (two 60 mg capsules) of fexofenadine hydrochloride within 15 minutes of taking an aluminum magnesium hydroxide antacid (Maalox) reduced the AUC and peak plasma concentration of fexofenadine by 41% and 43%, respectively. Therefore, the manufacturer states that fexofenadine (alone or in fixed-dose combination with pseudoephedrine hydrochloride) should not be taken with aluminum and magnesium antacids within a short period. Fruit juices (grapefruit juice, orange juice, apple juice) may reduce the bioavailability and systemic exposure of fexofenadine. Clinical studies have shown that, compared with water, co-administration of fexofenadine hydrochloride with grapefruit or orange juice significantly increased the area of wheals and erythema; similar effects have been reported with other fruit juices (e.g., apple juice). The clinical significance of these observations is unclear. Based on population pharmacokinetic analysis of data from studies involving the simultaneous administration of grapefruit or orange juice, as well as bioequivalence studies, the bioavailability of fexofenadine was reduced by 36%. Therefore, to maximize the therapeutic effect of fexofenadine, the manufacturer recommends administration 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 Receptor Antagonist
Antihistamine
Fexofenadine is indicated for the relief of symptoms associated with seasonal allergic rhinitis, such as sneezing, runny nose, itchy eyes, nose, and throat, and red, watery eyes. /US Product Label Includes/
Fexofenadine is indicated for the treatment of uncomplicated skin manifestations of chronic idiopathic urticaria. It significantly reduces itching and the number of wheals. /US Product Label Includes/
Drug Warnings

In controlled clinical studies in patients aged 12 years and older with allergic rhinitis, drowsiness or fatigue occurred in 1.3% of patients receiving oral fexofenadine hydrochloride 60 mg twice daily or placebo, compared to 0.9% in the placebo group. In these studies, headache was reported in 10.6% and 7.5% of patients receiving fexofenadine hydrochloride 180 mg once daily (in regular tablet form) or placebo, respectively. In a controlled study of children aged 6–11 years with seasonal allergic rhinitis, treatment with fexofenadine hydrochloride 30 mg twice daily or placebo resulted in headache incidence rates of 7.2% and 6.6%, and pain incidence rates of 2.4% and 0.4%, respectively. Patients taking fexofenadine hydrochloride experienced sleep disturbances, insomnia, or sinusitis. In a controlled clinical study, the incidence of nausea and dyspepsia in patients taking oral fexofenadine 60 mg twice daily was 1.6% and 1.3%, respectively, compared to 1.5% and 0.6% in the placebo group. Clinical data from over 2000 patients indicate that fexofenadine hydrochloride does not have the cardiotoxicity of its parent drug, terfenadine. In a controlled clinical study of 714 patients with seasonal allergic rhinitis taking 60–240 mg of fexofenadine hydrochloride twice daily, no statistically significant increase in the mean QT interval correction rate (QTc) was found. Furthermore, in 231 healthy subjects, no statistically significant increase in the mean QTc was observed with once-daily administration of 240 mg fexofenadine hydrochloride for one year. Even at doses exceeding the above criteria (e.g., 40 patients with 400 mg twice daily for 6 days; 32 patients with 690 mg twice daily for approximately one month; 87 patients with a single dose of 800 mg), no statistically significant mean increase in the QTc interval or other ECG abnormalities was reported in healthy adults or patients with seasonal allergic rhinitis. For more complete data on drug warnings for fexofenadine (15 in total), please visit the HSDB record page.

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Pharmacodynamics
Fexofenadine relieves allergy symptoms by antagonizing the action of histamine (an endogenous compound that primarily causes allergy symptoms). Fexofenadine has a relatively long duration of action (approximately 24 hours), allowing it to be taken once or twice daily; its rapid absorption allows it to take effect within 1–3 hours. Fexofenadine should not be taken with fruit juice, as this may affect 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.)