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
Based on mass balance studies using terfenadine labeled with 14C, the oral absorption rate of terfenadine is estimated to be at least 70%. Although at least 70% of the oral dose of terfenadine is rapidly absorbed from the gastrointestinal tract, the drug undergoes extensive (99%) first-pass metabolism in the liver and gastrointestinal tract. Therefore, in healthy individuals, typically only a very small amount (10 ng/mL or less) of the drug enters the systemic circulation unchanged after oral administration. In some cases, elevated plasma terfenadine concentrations (above 10 ng/mL) have been reported in seemingly healthy individuals after oral administration, without a significant risk of accumulation of the unchanged drug. Significant individual differences (up to five-fold) in peak plasma concentrations have been reported even with the same oral dose of terfenadine, likely due to individual differences in first-pass metabolism and/or enterohepatic circulation. The absolute bioavailability of oral terfenadine is unknown. When terfenadine is administered orally, its pharmacokinetics are linear at doses up to 180 mg. Food may slightly affect the absorption rate, but does not appear to affect the extent of gastrointestinal absorption of terfenadine. Peak plasma concentrations occur approximately 1–2 hours after a single oral dose of 60 mg terfenadine (tablets or suspension). For more complete data on the absorption, distribution, and excretion of terfenadine (17 items in total), please visit the HSDB records page. Metabolism/Metabolites Hepatitis Although the exact metabolic pathway of terfenadine is not fully understood, the drug is extensively metabolized in the liver primarily via the cytochrome P-450 microsomal enzyme system (including CYP3A4), and minimally metabolized in the gastrointestinal mucosa via CYP3A, mainly through oxidation. The terminal methyl group binds to fexofenadine and, through N-dealkylation of the butanol side chain, generates a piperidine methanol derivative (α,α-diphenyl-4-piperidinemethanol). Small amounts of other hydroxylated metabolites were also detected, but their exact structures have not been elucidated.
Studies have shown that fexofenadine, the major metabolite of terfenadine, may be the reason for its antihistamine effect, as only trace amounts (10 ng/mL or less) of the original drug are usually detected in plasma after oral administration of terfenadine to healthy individuals. Piperidine methanol derivatives lack in vivo and in vitro antihistamine activity.
Terfenadine (Seldane) is extensively metabolized to azaheptanol and terfenadine alcohol. Terfenadine alcohol is subsequently metabolized to azaheptanol and terfenadine acid. Although testosterone 6β-hydroxylase (CYP3A(4)) has been shown to be the major enzyme in the first step of terfenadine biotransformation (to azaheptanol and terfenadine alcohol), the enzymes catalyzing subsequent metabolic steps of terfenadine alcohol to azaheptanol and terfenadine acid have not been identified. This study aimed to determine the role of cytochrome P450 isoenzymes in the biotransformation of terfenadine and its alcohols. Therefore, we incubated terfenadine and its alcohol with 10 independent liver microsomal samples with identified major isoenzyme activities. High-performance liquid chromatography (HPLC) was used for quantitative analysis of the metabolites and parent drug. The results showed that the formation of terfenadine into azaheptanol and terfenadine alcohol was mainly catalyzed by the CYP3A(4) isoenzyme, and the reaction rate ratio… the ratio of terfenadine alcohol to azaheptanol was 3:1. The following studies further confirmed the involvement of CYP3A(4) in the metabolism of terfenadine: a) Ketoconazole and trazomycin (two CYP3A(4) specific inhibitors) inhibited the formation of terfenadine alcohol; b) the time course of terfenadine alcohol formation catalyzed by cloned human CYP3A(4). When terfenadine alcohol was used as a substrate, the CYP3A(4) isoenzyme could also catalyze the formation of terfenadine acid and azaheptanol. However, the formation rate of the terfenadine acid metabolite was almost 9 times that of azaheptanol. The net ratio of terfenadine acid to azacycloheptanol is 2:1. Terfenadine is a prodrug, normally completely metabolized in the liver by cytochrome P450 CYP3A4 isoenzymes to its active form, fexofenadine. Because terfenadine is almost immediately and completely metabolized by the liver after leaving the intestine, it is usually undetectable in plasma. (Wikipedia) Half-life: 3.5 hours

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Biological half-life
3.5 hours
After twice-daily oral administration of 60 mg terfenadine, the steady-state mean elimination half-lives of unchanged terfenadine and its carboxylic acid metabolite (fexofenadine) are 16.4 hours and 20.2 hours, respectively.
Elimination half-life: 20.3 hours

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 compound. In the United States, due to its potential to prolong the QT interval and cause arrhythmias, terfenadine was replaced by fexofenadine in the 1990s. Terfenadine is a prodrug that is metabolized in the intestine by CYP3A4 to its active form, fexofenadine, a selective histamine H1 receptor antagonist with antihistamine activity and no sedative effect. The active metabolite of terfenadine competitively binds to peripheral H1 receptors, thereby stabilizing the receptor's inactive conformation. This blocks the common allergic reaction triggered by mast cell degranulation, and the subsequent release of various inflammatory mediators such as interleukins, prostaglandins, and leukotriene precursors, thus preventing the activation of pro-inflammatory pathways. Terfenadine is only present in individuals who have used or taken the drug. In the United States, due to its potential to prolong the QT interval and cause arrhythmias, terfenadine was replaced by fexofenadine in the 1990s. Terfenadine competitively binds to H1 receptors in the smooth muscle of the gastrointestinal tract, uterus, large blood vessels, and bronchi with histamine. This reversible binding of terfenadine to H1 receptors inhibits the formation of skin edema, erythema, and pruritus induced by histamine activity. Because the drug does not readily cross the blood-brain barrier, its inhibitory effect on the central nervous system is minimal. A selective histamine H1 receptor antagonist without central nervous system depressant activity. This drug was previously used to treat allergic diseases but was discontinued due to causing long QT syndrome. Indications: For the treatment of allergic rhinitis, hay fever, and allergic dermatitis. Mechanism of Action: Terfenadine competitively binds to H1 receptors in the smooth muscle of the gastrointestinal tract, uterus, large blood vessels, and bronchi with histamine. This reversible binding of terfenadine to H1 receptors inhibits skin edema, erythema, and pruritus induced by histamine activity. Because the drug does not readily cross the blood-brain barrier, its inhibitory effect on the central nervous system is minimal. Terfenadine appears to have a dual effect on histamine H1 receptors. In vitro studies have shown that at concentrations of 15–47 ng/mL, terfenadine competitively antagonizes histamine; however, at higher concentrations (150–470 ng/mL), the antagonism is relatively irreversible. Experimental evidence suggests that the drug has specific and selective antagonistic activity against histamine H1 receptors, and that it binds slowly to the H1 receptors to form a stable complex, from which it then slowly dissociates. These findings indicate that terfenadine's antagonistic effect on histamine is persistent and usually irreversible, primarily due to the slow dissociation of the drug from the H1 receptors. Unlike many other antihistamines, pharmacological studies have shown that terfenadine does not exhibit significant anticholinergic or antiserotonergic activity at commonly used antihistamine doses. However, in clinical trials, terfenadine showed no difference in the frequency of observed anticholinergic effects (e.g., dry nose, mouth, pharynx, and/or lips) compared to other antihistamines (such as chlorpheniramine, kemastine, and dextrochlorpheniramine). Terfenadine also did not exhibit significant α- or β-adrenergic blocking activity or histamine H2 receptor antagonism. Terfenadine can increase bladder capacity in individuals with normal bladder function as well as in some patients with neurogenic bladder and detrusor overactivity, possibly through its antagonistic effect on detrusor H1 receptors; this effect appears to exhibit diurnal variation, being most pronounced at night. The cardiotoxic mechanisms of some “non-sedating” antihistamines, including terfenadine, are currently unclear, and these mechanisms appear to contradict the expected results of cardiac histamine H1 receptor studies; therefore, some studies suggest that H3 receptors (mediating regulatory feedback mechanisms) may be involved. Limited animal model evidence suggests that the cardiotoxicity of terfenadine may be at least partly due to its blocking of potassium channels involved in cardiomyocyte repolarization (i.e., delayed rectifier potassium currents, IK). In some animal studies using fexofenadine, no blocking of potassium channels involved in cardiomyocyte repolarization was observed, which may indicate that fexofenadine is not cardiotoxic. Furthermore, in in vitro studies, concentrations of fexofenadine up to 1.0 × 10⁻⁵ M had no effect on delayed rectifier potassium channels cloned from the human heart. Unlike other antihistamines, the cardiac effects of certain “non-sedating” antihistamines (including terfenadine) appear unlikely to be caused by anticholinergic and/or local anesthetic effects. In monocyte populations, basophils were stimulated with allergens (anti-immunoglobulin E (anti-IgE), C5a, or formylmethylleucylphenylalanine (FMLP)) with or without short-term pre-incubation with interleukin-3 (IL-3) and then with escalating concentrations of terfenadine. At doses of 0.1–1 μg/mL, terfenadine inhibited histamine release and the production of thioleukotrienes (leukotrienes C4, D4, and E4) in basophils stimulated by IgE-dependent triggers. However, at concentrations above 10 μg/mL, terfenadine induced histamine release but inhibited leukotriene production, likely due to its cytotoxic effects. Conversely, in eosinophils, terfenadine appears to inhibit leukotriene production, which is only triggered by FMLP at concentrations above 10 μg/mL (a concentration toxic to at least basophils). In a double-blind, placebo-controlled study, 15 allergic patients underwent skin provocation tests with specific allergens and histamine before and at 3 days, 2 weeks, and 4 weeks after treatment with terfenadine (120 mg/day for 3 consecutive days). Skin responses were visually assessed and dynamically tracked using thermal imaging. Terfenadine significantly reduced both immediate and delayed responses. In some patients, delayed histamine responses were observed on thermal imaging.

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.)