Caspase-4; Caspase-2; Caspase-9; Ca2+ homeostasis; H1 histamine receptor

Terfenadine ((±)-Terfenadine) (4-20 μM; 24 hours) causes A375 melanoma cells to undergo dose- and time-dependent apoptosis. After 24 hours of TEF treatment in complete medium, the IC50 for A375 cells, Hs294T cells, and HT144 cells was 10.4, 9.9, and 9.6, respectively[2].Terfenadine (2–10 μM; 8 h) causes dose-dependent cytotoxicity[2]. Terfenadine (10 M; 8 hours) significantly increases the number of autophagic vacuoles in the cytoplasm of cells with double and multiple membranes. Inducing autophagy with terfenadine involves both ROS-dependent and -independent mechanisms[2].

In chemo-resistant NSCLC xenograft models, terfenadine (p.o.; 40 mg/kg; for 16 days) significantly slows the rate at which tumors grow while also enhancing the anti-cancer effect of EPI[3].

Absorption, Distribution and Excretion
On the basis of a mass balance study using 14C labeled terfenadine the oral absorption of terfenadine was estimated to be at least 70%
Although at least 70% of an oral dose of terfenadine is rapidly absorbed from the GI tract following oral administration, the drug undergoes extensive (99%) first-pass metabolism in the liver and GI tract, with minimal (10 ng/mL or less)amounts of an orally administered dose of the drug generally appearing to reach systemic circulation unchanged in healthy individuals. In some cases, increased plasma terfenadine concentrations (exceeding 10 ng/mL) following oral administration of the drug were reported in apparently healthy individuals with no identifiable risk for systemic accumulation of unchanged drug; ... Considerable interindividual variations (up to five-fold) in peak plasma concentrations have been reported with the same oral dose of terfenadine, possibly resulting from interindividual differences in first-pass metabolism and/or enterohepatic circulation of the drug.
The absolute bioavailability of oral terfenadine is not known. When administered orally, terfenadine exhibits linear pharmacokinetics up to doses of 180 mg.
Food may effect the rate slightly but does not appear to effect the extent of GI absorption of terfenadine.
Following oral administration of a single 60-mg terfenadine dose (as tablet or suspension, peak plasma concentrations of the drug occur at about 1-2 hours.
For more Absorption, Distribution and Excretion (Complete) data for TERFENADINE (17 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic
Although the exact metabolic fate of terfenadine is not clearly established, the drug is extensively metabolized in the liver by cytochrome P-450 microsomal enzyme system including CYP3A4 and to a lesser extent in the GI mucosa by CYP3A, principally via oxidation of the terminal methyl group to fexofenadine and via N-dealkylation of the substituted butanol side chain to a piperidine carbinol derivative (alpha,alpha-diphenyl-4-piperidinemethanol). Small amounts of other hydroxylated metabolites also have been detected, but their exact structures have not been elucidated.
It has been suggested that fexofenadine, the main metabolite of terfenadine, may be responsible for the antihistaminic effect of terfenadine since only minimal amounts (10 ng/mL or less) of unchanged drug usually are detected in plasma following oral administration of terfenadine in healthy individuals. The piperidine carbinol derivative lacks both in vivo and in vitro antihistaminic activity.
Terfenadine (Seldane) undergoes extensive metabolism to form azacyclonol and terfenadine alcohol. Terfenadine alcohol is subsequently metabolized to azacyclonol and terfenadine acid. Although testosterone 6 beta-hydroxylation (CYP3A(4)) has been shown to be the principal enzyme involved in the first step in terfenadine's biotransformation (formation of azacyclonol and terfenadine alcohol), the enzymes catalyzing the subsequent metabolic steps in the conversion of terfenadine alcohol to azacyclonol and terfenadine acid have not been identified. The purpose of these studies was to determine the role of cytochrome P450 isoforms in the biotransformation of terfenadine and terfenadine alcohol. To this end, both terfenadine and its alcohol were incubated with 10 individual human liver microsomal samples that have been characterized for major isozyme activities. The metabolites and parent drugs were quantified by HPLC. The formation of azacyclonol and terfenadine alcohol from terfenadine is confirmed to be catalyzed predominantly by CYP3A(4) isozyme, and the ratio of the rate of terfenadine alcohol formation to that of azacyclonol is 3:1. Involvement of the CYP3A(4) in terfenadine metabolism was further confirmed by the following studies: a) inhibition of terfenadine alcohol formation by ketoconazole and troleandomycin, two specific inhibitors of CYP3A(4), and b) time course of terfenadine alcohol formation by cloned human CYP3A(4). When terfenadine alcohol was used as substrate, both the terfenadine acid and azacyclonol formation were also catalyzed by CYP3A(4) isozyme. However, the rate of formation of the terfenadine acid metabolite is almost 9 times faster than that of azacyclonol. The net ratio of terfenadine acid to azacyclonol is 2:1.
Terfenadine is a prodrug, generally completely metabolized to the active form fexofenadine in the liver by the enzyme cytochrome P450 CYP3A4 isoform. Due to its near complete metabolism by the liver immediately after leaving the gut, terfenadine normally is not measurable in the plasma. (Wikipedia)
Half Life: 3.5 hours

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Biological Half-Life
3.5 hours
Following multiple oral dosing of 60 mg of terfenadine twice daily, steady-state mean elimination half-lives of unchanged terfenadine and the carboxylic acid metabolite (fexofenadine) were 16.4 and 20.2 hours, respectively.
Elimination half-life: 20.3 hr

Protein Binding
70%

[1]. Molecular determinants of hERG channel block by terfenadine and cisapride. J Pharmacol Sci. 2008 Nov;108(3):301-307.

[2]. Terfenadine induces apoptosis and autophagy in melanoma cells through ROS-dependent and -independent mechanisms. Apoptosis. 2011 Dec;16(12):1253-67.

[3]. Pharmacol Res . 2017 Oct;124:105-115.

Terfenadine is a diarylmethane.
In the U.S., Terfenadine was superseded by fexofenadine in the 1990s due to the risk of cardiac arrhythmia caused by QT interval prolongation.
Terfenadine is a prodrug that is metabolized by intestinal CYP3A4 to the active form fexofenadine, a selective histamine H1-receptor antagonist with antihistaminic and non-sedative effects. Terfenadine's active metabolite competitively binds peripheral H1-receptors, thereby stabilizing an inactive conformation of the receptor. Consequently, usual allergic responses as a result of mast-cell degranulation followed by the release of multiple inflammatory mediators, such as interleukins, prostaglandins, and leukotriene precursors, are blocked, thereby preventing the triggering of pro-inflammatory pathways.
Terfenadine is only found in individuals that have used or taken this drug. In the U.S., Terfenadine was superseded by fexofenadine in the 1990s due to the risk of cardiac arrhythmia caused by QT interval prolongation.Terfenadine competes with histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of terfenadine to H1-receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier, CNS depression is minimal.
A selective histamine H1-receptor antagonist devoid of central nervous system depressant activity. The drug was used for ALLERGY but withdrawn due to causing LONG QT SYNDROME.

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Drug Indication
For the treatment of allergic rhinitis, hay fever, and allergic skin disorders.

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Mechanism of Action
Terfenadine competes with histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of terfenadine to H1-receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier, CNS depression is minimal.
... Terfenadine appears to have a dual effect on histamine H1-receptors. In vitro studies indicate that terfenadine competitively antagonizes the actions of histamine at concentrations of 15-47 ng/mL, while a relatively irreversible antagonism occurs at higher concentrations (ie, 150-470 ng/mL). Experimental evidence indicates that the drug exhibits a specific and selective antagonism of histamine H1-receptors and that the drug slowly binds to the H1-receptor and forms a stable complex from which it subsequently slowly dissociates. These finding suggest that the prolonged and generally irreversible nature of terfenadin's antagonism of histamine results principally from the drugs slow dissociation from the H1-receptors.
Unlike many other antihistamines, terfenadine does not possess appreciable anticholinergic or antiserotonergic effects at usual antihistaminic doses in pharmacologic studies. However, in clinical trials there was no difference in the frequency of anticholinergic-like effects (eg, dryness of the nose, mouth, throat and/or lips)observed with terfenadine or other antihistamines (ie, chlopheniramine, clemastine, dexchlorpheniramine). Terfenadine also does not exhibit any appreciable alpha or beta-adrenergic blocking activity or histamine H2-receptor antagonism.
Terfenadine has increased urinary bladder capacity in individuals with normal bladder function and in some patients with neurogenic bladder and overactive detrusor muscle function, probably via a histamine H1-antagonist effect on the detrusor muscle; this effect appears to vary diurnally, being maximal at night.
The mechanism of the cardiotoxic effects of certain "nonsedating" antihistamines including terfenadine currently is not understood, and would appear to be contrary to what would be expected from studies on cardiac histamine H1-receptors; therefore, the possibility that H3-receptors (mediating a regulatory feedback mechanism) may be involved has been suggested. Limited evidence from animal models using terfenadine suggests that the cardiotoxic effects of the drug may result at least in part from blockade of the potassium channel involved in repolarization of cardiac cells (ie, blockade of the delayed rectifier potassium current IK). In some animal studies using fexofenadine, no blockade of the potassium channel involved in repolarization of cardiac cells was observed which may indicate a lack of fexofenadine-induced cardiotoxicity. In addition,in in vitro studies using fexofenadine, no effect was observed on delayed rectifier potassium channel cloned from human heart at fexofenadine concentrations up to 1.0X10-5M. Unlike with other antihistamines, anticholinergic and/or local anesthetic effects appear to be unlikely cause of the cardiac effects of certain "nonsedating" antihistamines, including terfenadine.
Basophils in mononuclear cell populations were challenged with allergens, anti-immunoglobulin E (anti-IgE), C5a or formyl-methyl-leucyl-phenylalanine (FMLP), with or without a short pre-incubation with interleukin-3 (IL-3), in the presence of increasing concentrations of terfenadine. At doses of 0.1-1 ug/mL, terfenadine inhibits histamine release and generation of the sulfidoleukotrienes, leukotriene C4, D4 and E4 in basophils challenged with an IgE-dependent trigger. At concentrations above 10 ug/mL, however, terfenadine induces the histamine release but abolishes the formation of leukotrienes, and this may be due to a cytotoxic effect. In eosinophils, by contrast, terfenadine appears to inhibit the production of leukotrienes by eosinophils, triggered by FMLP only at concentrations above 10 ug/mL (which are toxic to basophils at least). In a double-blind, placebo-controlled study, 15 allergic patients were given skin challenges with specific allergen and with histamine, before and at 3 days, 2 and 4 weeks after treatment with terfenadine (120 mg/day for 3 days). The skin reactions were evaluated visually and followed kinetically by thermography. Terfenadine caused a significant decrease in both the immediate and late-phase reactions. Late-phase reactions to histamine were shown with thermography in some of the patients tested.

C32H41NO2

471.685

471.313

C, 81.48; H, 8.76; N, 2.97; O, 6.78

50679-08-8

50679-08-8

5405

White to off-white solid powder

1.1±0.1 g/cm3

626.8±55.0 °C at 760 mmHg

145-152 °C

306.9±30.2 °C

0.0±1.9 mmHg at 25°C

1.580

6.51

2

3

9

35

582

0

OC(C1=CC=C(C(C)(C)C)C=C1)CCCN2CCC(C(C3=CC=CC=C3)(O)C4=CC=CC=C4)CC2

GUGOEEXESWIERI-UHFFFAOYSA-N

InChI=1S/C32H41NO2/c1-31(2,3)26-18-16-25(17-19-26)30(34)15-10-22-33-23-20-29(21-24-33)32(35,27-11-6-4-7-12-27)28-13-8-5-9-14-28/h4-9,11-14,16-19,29-30,34-35H,10,15,20-24H2,1-3H3

1-(4-tert-butylphenyl)-4-[4-[hydroxy(diphenyl)methyl]piperidin-1-yl]butan-1-ol

BRN 5857899; BRN-5857899; BRN5857899; Terfen; Seldane; Terfenadine

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)

DMSO: ~94 mg/mL (199.3 mM)
Ethanol: ~27 mg/mL (~57.2 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.30 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 (5.30 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 (5.30 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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 (Please use freshly prepared in vivo formulations for optimal results.)