Histamine H₁ Receptor

Astemizole is an H1-histamine receptor antagonist with a long duration of action permitting once daily administration. Its efficacy in seasonal and perennial allergic rhinitis has been convincingly demonstrated, and several comparative studies suggest that astemizole is at least as effective as some other H1-histamine receptor antagonists. A few smaller studies have shown beneficial effects on the symptoms of allergic conjunctivitis and chronic urticaria (but not atopic dermatitis). While astemizole appears to share with other H1-histamine receptor antagonists a tendency to increase appetite and cause weight gain after prolonged use, it offers the important advantage of an absence of significant central nervous system depression or anticholinergic effects with usual doses. Thus, astemizole offers a worthwhile improvement in side effect profile over 'traditional' H1-histamine receptor antagonists, especially in patients bothered by the sedative effects of these drugs[2].

Astemizole (po, 10 and 30 mg/kg) and (iv, 1 and 3 mg/kg) had no effect on respiratory rate, heart rate, or blood glucose, even at the high doses of 30 mg/kg and 3 mg/kg. It also had no effect on breast cancer and exercise capacity in marmosets of average weight. However, astemizole at 30 mg/kg (po) and 1 mg/kg (iv) can prolong the QT interval and induce premature ventricular contractions [3]. Astemizole (po, 3) and 30 mg/kg) at a dose of 3 mg/kg, preperfume control values (C) for ventricular rate, QT interval, and QTcF were 31 beats/min, 319 ms, and 256, whereas these were 31 beats/min, 331 ms, and 270 respectively at a dose of 30 mg/kg in mice. In addition, astemizole at a dose of 30 mg/kg (po) may cause torsade de pointes ventricular tachycardia by inhibiting hERG K+ channels [4].

Binding characteristics of astemizole were studied in vitro in various receptor binding models and in vivo by determining the occupancy of histamine H1 receptors in guinea pig lung and cerebellum. In vitro, astemizole was found to have a high affinity for histamine H1 receptors, but great difficulties were encountered in proving this because of its high affinity for nonspecific binding sites. Since the equilibrium conditions were not reached in vitro, the real affinity of astemizole remains unclear and its receptor profile must be interpreted with caution. Nevertheless, the drug is certainly much more potent on histamine H1 receptors than on serotonin S2 and adrenergic alpha 1-receptors. Moreover, it was found to be devoid of antimuscarinic and antidopaminergic properties. The most striking property of this drug is its extremely slow dissociation rate from H1 receptors when assayed in vitro using [3H]-pyrilamine. Ex vivo experiments were performed in guinea pigs; astemizole was given orally to the animals, and the occupancy of H1 receptors in the lung and the cerebellum was determined in vitro by the [3H]-pyrilamine binding assay. Astemizole was found to occupy H1 receptors in lung at very low doses. Here again the most striking receptor binding property was its very long duration. The occupancy of H1 receptors in lung began to decline only 4-6 days after administration of the drug. However, there was a marked difference between the occupancy of peripheral and central receptors; indeed, in contrast to pyrilamine, astemizole at pharmacological doses did not reach the H1 receptors in the cerebellum, presumably because the drug does not readily cross the blood-brain barrier[1].

The purpose of this study was to evaluate a telemetry system for examining the cardiovascular system in the conscious common marmoset. Parameters obtained were blood pressure, heart rate, respiratory rate, ECG, body temperature and locomotor activity, and these were continuously recorded on a data recorder via the telemetry system and then processed by a computerized system. Diurnal rhythms of blood pressure, heart rate, body temperature and locomotor activity were observed in this system. We studied the effects of astemizole (antihistamine) and nicardipine (Ca2+ channel blocker) on cardiovascular parameters. Astemizole at 30 mg/kg (p.o.) and at 1 to 3 mg/kg (i.v.), prolonged QT interval and induced ventricular extrasystole. Torsades de pointes occurred in one of three cases at 3 mg/kg (i.v.) and 30 mg/kg (p.o.), while it did not affect the blood pressure, respiratory rate and body temperature. Nicardipine at 30 mg/kg (p.o.) caused sustained hypotension and tachycardia. These results demonstrate the usefulness of the telemetry system using the common marmoset for evaluating the cardiovascular effects of drugs under physiological conditions.[3]

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Since astemizole in an oral dose of 50 mg/kg/day was recently reported to exert anti-cancer effect in mice, we evaluated its proarrhythmic potential using the atrioventricular block dogs in order to clarify its cardiac safety profile. An oral dose of 3 mg/kg prolonged the QT interval without affecting the QTc (n = 4), whereas that of 30 mg/kg increased the short-term variability of repolarization and induced premature ventricular contractions in each animal, resulting in the onset of torsade de pointes in 1 animal (n = 4). Thus, proarrhythmic dose of astemizole would be lower than anti-cancer one, limiting its re-profiling as an anti-cancer drug.[4]

Absorption, Distribution and Excretion
Rapidly absorbed from the gastrointestinal tract.
Protein binding: 96%
Time to peak concentration: Within 1 hour.
It is not known whether astemizole is distributed into human breast milk. Astemizole is distributed into the milk of dogs.
Following concomitant administration of astemizole with food, oral bioavailability of the drug is decreased by 60%.

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Metabolism / Metabolites
Almost completely metabolized in the liver and primarily excreted in the feces.
Orally administered astemizole is well absorbed but undergoes an extensive first-pass metabolism to O-desmethylastemizole. Desmethylastemizole is formed in the human microsomal systems of the small intestine as well as the liver, which suggests the role of cytochromes P450 (P450s) in the first-pass metabolism of astemizole. Human P450s involved in the O-demethylation of astemizole have, however, not been identified, and the involvement of twelve known drug-metabolizing P450s were denied. During the course of the P450 identification study, higher activities of the astemizole O-demethylation in the rabbit small intestine than in the liver (about 3-fold) were found. These data suggest the possible involvement of CYP2J, since P450 included in this subfamily is dominantly expressed in the small intestine of rabbits. ...
... Three metabolites of astemizole were detected in a /human/ liver microsomal system, i.e. desmethylastemizole (DES-AST), 6-hydroxyastemizole (6OH-AST) and norastemizole (NOR-AST) at the ratio of 7.4:2.8:1. Experiments with recombinant P450s and antibodies indicate a negligible role for CYP3A4 on the main metabolic route of astemizole, i.e. formation of DES-AST, although CYP3A4 may mediate the relatively minor metabolic routes to 6OH-AST and NOR-AST. Recombinant CYP2D6 catalyzed the formation of 6OH-AST and DES-AST. Studies with human liver microsomes, however, suggest a major role for a mono P450 in DES-AST formation. ...
Second-generation, relatively nonsedating histamine H1-receptor antagonists (H1-RA) are extensively used worldwide for the symptomatic treatment of allergic rhinoconjunctivitis and chronic urticaria. Information about the pharmacokinetics and pharmacodynamics of these medications, while still incomplete, is now sufficient to permit optimisation of therapy. Published pharmacokinetic and pharmacodynamic information on these H1-RA is summarised here, and areas where more data are required are delineated. Serum concentrations of most second-generation H1-RA are relatively low, and are usually measured by radioimmunoassay. After oral administration, peak concentrations are observed within 2 or 3 h. Bioavailability has not been well studied, due to the lack of intravenous formulations. Most H1-RA are metabolised in the hepatic cytochrome P450 system: terfenadine, astemizole, loratadine, azelastine, and ebastine have 1 or more active metabolites which are present in serum in higher concentrations than the respective parent compound, and therefore can be measured by high performance liquid chromatography. Cetirizine, an active metabolite of the first generation H1-receptor antagonist hydroxyzine, is not further metabolised to any great extent in vivo, and is eliminated via renal excretion. Levocabastine is also eliminated primarily by excretion. Serum elimination half-life values differ greatly from 1 H1-RA to another, and are 24 h or less for terfenadine, astemizole, loratadine, cetirizine, azelastine and ebastine, and the active metabolites of terfenadine, loratadine and ebastine. The active metabolite of azelastine (demethylazelastine) has a serum elimination half-life value of about 2 days, while that of astemizole (demethyl-astemizole) has a value of 9.5 days. From the few published studies in which the apparent volumes of distribution of the second-generation H1-RA have been calculated, it appears that tissue distribution is extensive. In children, the half-lives of H1-RA are generally shorter than are found in adults; there is no published information on the pharmacokinetics of astemizole, loratadine, azelastine, or ebastine in children. In some elderly adults, terfenadine, loratadine and cetirizine may have longer half-lives than in young healthy adults. There is little published data on the pharmacokinetics of the second-generation H1-RA in patients with impaired hepatic function. The half-life of cetirizine is prolonged in those with impaired renal function. There is a paucity of information on the pharmacokinetics of H1-RA in neonates, in pregnancy or during lactation.
The antiallergic effects of astemizole and its metabolites were studied in rats and guinea pigs. All of the metabolites of astemizole tested were more active than the parent compound in inhibiting contraction of the ileum and bronchoconstriction induced by histamine in guinea pigs. Desmethylastemizole was about the same as astemizole in inhibiting mepyramine binding in guinea pig cerebellum. In heterologous passive cutaneous anaphylaxis (PCA) and homologous PCA, the metabolites caused almost equipotent inhibition to that seen with astemizole. No H2-antagonistic activity was seen with astemizole or desmethylastemizole.
Astemizole has known human metabolites that include 6-desmethylastermizole, norastemizole, 2-(4-hydroxyphenyl)acetaldehyde, and 6-Hydroxyastemizole.
It is metabolized by CYP3A4. [Wikidpedia]. Almost completely metabolized in the liver and primarily excreted in the feces.
Half Life: 1 day

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Biological Half-Life
1 day
Elimination: Astemizole (plus hydroxylated metabolites) - Mutiple doses, biphasic with an initial half life of 7 to 9 days (with plasma concentrations being reduced by 75% within this phase) and a terminal half life of about 19 days.
With multiple doses: 7 to 9 days (initial); 19 days (terminal).
The active metabolite of astemizole (demethyl-astemizole) has a value of 9.5 days.

Toxicity Summary
Astemizole competes with histamine for binding at H₁-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of astemizole 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 and preferentially binds at H1 receptors in the peripehery rather than within the brain, CNS depression is minimal. Astemizole may also act on H₃-receptors, producing adverse effects.

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Protein Binding
96.7%

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Toxicity Data
LD50: 2052mg/kg (Mouse) (A308)

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Interactions
The effect of a standard regimen of dirithromycin, a macrolide antibiotic, on the single-dose pharmacokinetics of the H (1) receptor blocker astemizole was evaluated in a sample of 18 healthy young adults (nine males and nine females). The study was conducted in a two-way cross-over fashion after the subjects had been randomly given either dirithromycin (two 250 mg tablets) or placebo (two tablets) every morning for 10 days. On the morning of the fourth dose of either dirithromycin or placebo each subject ingested a single 30-mg oral dose (three 10-mg tablets) of astemizole. The disposition kinetics of both astemizole and its major metabolite, N-desmethylastemizole, were characterized after measuring the concentrations of both analytes in the serum fraction of serial blood samples collected for 14 days after the astemizole dose. In addition, corrected QTc intervals were estimated from electrocardiogram rhythm strips that were run 24 hours prior to the astemizole dose, 12 hours after the astemizole dose, and after the last treatment (dirithromycin or placebo) dose in both study periods. Pharmacokinetic parameters that were measured for both astemizole and N-desmethylastemizole during each treatment were: C(max), t(max), AUC (0-infinity), CL(oral), half-life, and volume of distribution (V). None of the parameters for N-desmethylastemizole was different when comparing data by ANOVA from the dirithromycin treatment period with that of the placebo treatment period. On the other hand, during dirithromycin treatment astemizole Cl(oral) was 34% slower, volume of distribution was 24% larger, and half-life was 84% longer. Generally, all QTc intervals did not appear to be affected by dirithromycin treatment. The changes in astemizole kinetics could not be attributed to its N-demethylation since the dispositional kinetics of N-desmethylastemizole were unaffected by dirithromycin. Therefore, it is difficult to ascertain the clinical significance of the changes in astemizole kinetics. Since there were no significant differences for mean QTc intervals and no effect of dirithromycin treatment on N-desmethylastemizole kinetics, it is unlikely that a standard regimen of dirithromycin would place a patient taking astemizole at an increased risk of torsade de pointes or related ventricular arrhythmias.
The effects of chemical agents on the metabolism of the antihistamine drug astemizole were investigated to evaluate drug-drug interactions. Chemical inhibitors of astemizole O-demethylation were screened using the small intestinal and liver microsomes from rabbit as an animal model for the first-pass metabolism of humans. In the rabbit small intestine, astemizole O-demethylation was clearly inhibited by ebastine, arachidonic acid, alpha-naphthoflavone, ketoconazole, tranylcypromine, troglitazone and terfenadine. In humans, these inhibitors also reduced microsomal astemizole O-demethylation in both the small intestine and liver. However, the inhibition rate of almost all these chemicals were clearly greater in the small intestine than in the liver. Thus, a different contribution of cytochrome p450 in each tissue is suggested. All the chemicals inhibited astemizole O-demethylation in recombinant CYP2J2 microsomes. The results suggest that CYP2J2 is involved in astemizole O-demethylation in both the human small intestine and liver; however, the contribution in the liver is lower than in the small intestine. The effects of the CYP2J2 inhibitors during first-pass metabolism may be more important in the small intestine than in the liver. Since all the inhibition profiles of astemizole O-demethylation were different in the liver and small intestine, involvement of another p450 in astemizole O-demethylation in human liver may be speculated. In the rabbit microsomal systems, the same metabolites found in humans were qualitatively detected and the inhibition profiles of the chemical agents in the microsomes resembled that of humans.
Concurrent use of astemizole with clarithromycin, erythromycin or troleandomycin is contraindicated; pending further evaluation, concurrent use of astemizole with other macrolide antibiotics, such as azithromycin, is not recommended.
The aim of this study was to evaluate the effects of astemizole given intraperitoneally /to mice/ singly or for 7 days on the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced convulsions in mice. The following antiepileptic drugs were administered intraperitoneally: valproate magnesium, carbamazepine, diphenylhydantoin and phenobarbital. Adverse effects were evaluated in the chimney test (motor performance) and passive avoidance task (long-term memory). Brain and plasma levels of antiepileptic drugs were measured by immunofluorescence. Astemizole (a single dose and following a 7-day treatment at 2-6 mg/kg) reduced the threshold for electroconvulsions, being without effect upon this parameter at lower doses. Astemizole (1 mg/kg) did not significantly alter the protective effect of antiepileptic drugs against maximal electroshock (after acute and 7-day administration). Also, acute astemizole (2 mg/kg) remained ineffective in this respect. Astemizole (2 mg/kg), following chronic administration, significantly reduced the protective efficacy of phenobarbital and diphenylhydantoin, reflected by an increase in their ED(50) values (50% effective dose necessary to protect 50% of animals tested against maximal electroshock) from 21.1 to 34.0 mg/kg and from 10.4 to 19.2 mg/kg, respectively. Astemizole (2 mg/kg) did not alter the protective activity of the remaining antiepileptic drugs. Moreover, astemizole (2 mg/kg) did not influence the free plasma levels and brain concentration of the studied antiepileptic drugs. Also, this H(1) receptor antagonist did not impair long-term memory or motor coordination when given acutely. However, 7-day treatment with astemizole (2 mg/kg) significantly decreased TD(50) (50% toxic dose required to induce motor impairment in 50% of animals) value of phenobarbital, being without effect on carbamazepine, valproate and diphenylhydantoin in this respect. Similarly, phenobarbital and diphenylhydantoin, administered alone at their ED(50)s against maximal electroshock, or combined with astemizole, disturbed long-term memory in mice. The results of this study indicate that astemizole may need to be used with caution in epileptic patients.
For more Interactions (Complete) data for ASTEMIZOLE (15 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral >2560 mg/kg
LD50 Rat sc 355 mg/kg
LD50 Rat iv 28 mg/kg
LD50 Mouse oral 2560 mg/kg
For more Non-Human Toxicity Values (Complete) data for ASTEMIZOLE (6 total), please visit the HSDB record page.

[1]. In vitro and in vivo binding characteristics of a new long-acting histamine H1 antagonist, astemizole. Mol Pharmacol. 1982 Mar;21(2):294-300.

[2]. Astemizole. A review of its pharmacodynamic properties and therapeutic efficacy. Drugs. 1984 Jul;28(1):38-61.

[3]. Development of telemetry system in the common marmoset--cardiovascular effects of astemizole and nicardipine. J Toxicol Sci. 2002 May;27(2):123-30.

[4]. Possibility as an anti-cancer drug of astemizole: Evaluation of arrhythmogenicity by the chronic atrioventricular block canine model. J Pharmacol Sci. 2016 Jun;131(2):150-3.

Therapeutic Uses
Anti-Allergic Agents; Histamine H1 Antagonists
Antihistaminic
Products containing astemizole were withdrawn from the US and Canadian markets by the manufacturer in June 1999.
Antihistamines are indicated in the prophylactic and symptomatic treatment of perennial and seasonal allergic rhinitis, vasomotor rhinitis, and allergic conjunctivitis due to inhalant allergens and foods. /Antihistamines/ NOTE: Products containing astemizole were withdrawn from the US and Canadian markets by the manufacturer in June 1999.
For more Therapeutic Uses (Complete) data for ASTEMIZOLE (7 total), please visit the HSDB record page.

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Drug Warnings
Astemizole /has/ been shown to have a number of adverse effects on the electrophysiology of the heart, including altered repolarization, notched inverted T waves, prominent TU waves, prolonged QT interval, first- and second-degree AV block, ventricular tachycardia or fibrillation, and torsades de pointes.
Astemizole /has/ been recognized in rare cases to induce the syndrome of torsades de pointes, i.e. QT interval prolongation and life-threatening ventricular tachycardia. /It/ was found to prolong cardiac repolarization when its metabolic elimination was impaired, such as by liver disease or drugs that inhibit the 3A family of cytochrome P450. In vitro studies indicate that this action is due to blockade of one or more of the cardiac potassium channels that determine the duration of the action potential.
Safe use of antihistamines during pregnancy has not been established; therefore, the drugs should not be used in women who are or may become pregnant unless the potential benefits justify the possible risks to the fetus. Some manufacturers caution that antihistamines should not be used during the third trimester because of the risk of severe reactions (e.g., seizures) to the drugs in neonates and premature infants. /Antihistamines/
Patients receiving astemizole ... should be instructed to take the drug only as needed an not to exceed the prescribed dosage. The manufacturer of astemizole states that patients should be advised not to use astemizole on an as-needed ("prn") basis for immediate relief of symptoms. In addition, while a loading-dose regimen previously was recommended when an accelerated onset of effect was sought, such a regimen no longer is recommended because of the risk of cardiotoxicity.
For more Drug Warnings (Complete) data for ASTEMIZOLE (8 total), please visit the HSDB record page.

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Pharmacodynamics
Astemizole is a second generation H₁-receptor antagonist. It does not significantly cross the blood brain barrier and therefore does not cause drowsiness or CNS depression at normal doses.

C28H31FN4O

458.57034

458.248

C, 73.34; H, 6.81; F, 4.14; N, 12.22; O, 3.49

68844-77-9

2247

White to off-white solid powder

1.2 g/cm3

627.3ºC at 760 mmHg

172.9ºC

333.2ºC

1.623

5.362

1

5

8

34

599

0

COC1=CC=C(C=C1)CCN2CCC(CC2)N=C3NC4=CC=CC=C4N3CC5=CC=C(C=C5)F

GXDALQBWZGODGZ-UHFFFAOYSA-N

InChI=1S/C28H31FN4O/c1-34-25-12-8-21(9-13-25)14-17-32-18-15-24(16-19-32)30-28-31-26-4-2-3-5-27(26)33(28)20-22-6-10-23(29)11-7-22/h2-13,24H,14-20H2,1H3,(H,30,31)

1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl]benzimidazol-2-amine

R 43512; Hismanal; R43512; astemizole; 68844-77-9; Hismanal; Histaminos; Paralergin; Laridal; Retolen; Astemison; Paralergin; R-43512; NSC 329963; NSC329963; NSC-329963; Astemizole; Histaminos; Laridal; Retolen

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: ~125 mg/mL (~272.6 mM)

Solubility in Formulation 1: ≥ 6.25 mg/mL (13.63 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 62.5 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: ≥ 6.25 mg/mL (13.63 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 62.5 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly.

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