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PubMed1991

Onset of action of astemizole.

Astemizole has been described to have a slow onset of action and this has to a large extent been attributed to its unusual pharmacokinetic profile. Yet, pharmacokinetically, there are no reasons why astemizole should not act within the first hours after intake, since plasma levels of unchanged astemizole are maximal within 40 min and there is fast tissue distribution. Animal pharmacology data show effective antihistamine activity with astemizole within 1 h after intake. Clinical data referring to the onset of action of astemizole with regard to symptom relief were available from 27 studies on over 7000 patients. These studies showed astemizole to provide symptom relief within 4 to 6 h of intake in 16-85% of patients, and within 24 h in 42-90% of patients; these figures are comparable to those reported for other new antihistamines. Comparative studies between astemizole and other new antihistamines (terfenadine, loratadine and cetirizine) indicated no or only minor differences in onset of clinical effect. Two recent studies compared astemizole to both terfenadine and loratadine under well-controlled circumstances. One was a pollen challenge study showing all three drugs to be able to reverse the challenge-induced effects within 1-3 h after intake. In the other, the mean time to relief of at least one rhinitis symptom was assessed as 18 min for astemizole, 24 min for terfenadine and 36 min for loratadine. Compared with the systemic decongestant pseudoephedrine, time to first relief of symptoms was similar for astemizole (4 h) and pseudoephedrine (3.5 h). Controlled clinical trials thus show astemizole to provide fast symptom relief. This was confirmed in patient surveys in Canada and Switzerland: over 80% of patients were very satisfied with astemizole and experienced onset of action within hours. In conclusion, astemizole results in symptom relief within hours after its administration. Its onset of action is not different from that of other nonsedating antihistamines and is also similar to that of pseudoephedrine.

Animals↗

PubMedDate not supplied

A study of the interaction between dirithromycin and astemizole in healthy adults.

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 QT (QT(c) ) 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 QT ( c ) 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 QT(c) 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.

Adolescent↗

PubMed2003

Interaction of astemizole, an H1 receptor antagonist, with conventional antiepileptic drugs in mice.

Histamine is one of the aminergic neurotransmitters, playing an important role in the regulation of a number of physiological processes. There are several subtypes of histamine receptors-H(1), H(2), H(3) and the recently discovered H(4). H(1) receptors exist on mast cells, basophils, enterochromaffin cells and in the central nervous system, being located postsynaptically. H(1) receptor antagonists, including classical antiallergy drugs, occasionally have been expected to induce convulsions in children and epileptics. The aim of this study was to evaluate the effects of astemizole-given intraperitoneally, singly or for 7 days on the anticonvulsant activity of antiepileptic drugs (AEDs) against maximal electroshock (MES)-induced convulsions in mice. The following AEDs 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 AEDs 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 AEDs against MES (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 MES) 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 AEDs. Moreover, astemizole (2 mg/kg) did not influence the free plasma levels and brain concentration of the studied AEDs. 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 MES, 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.

Animals↗

PubMed1997

Influence of itraconazole on the pharmacokinetics and electrocardiographic effects of astemizole.

AIMS: The aim of this study was to investigate the influence of chronic itraconazole treatment on the pharmacokinetics and cardiovascular effects of single dose astemizole in healthy subjects was studied. METHODS: Twelve male volunteers were taking orally 200 mg twice daily itraconazole or placebo for 14 days with a washout period of 4 weeks in between. Approximately 2 h after the morning dose of itraconazole or placebo on day 11, 10 mg astemizole was orally administered. The plasma concentrations of astemizole and desmethylastemizole were measured by radioimmunoassay up to 504 h after administration; electrocardiograms with analysis of the QTc interval were recorded up to 24 h post administration. RESULTS: Itraconazole treatment did not significantly change the peak concentration of astemizole (0.74 vs 0.81 ng ml-1) but it increased the area under the curve from 0 to 24 h (5.46 to 9.95 ng ml-1 h) and from 0 to infinity (17.4 to 48.2 ng ml-1 h), and the elimination half-life (2.1 to 3.6 days). The systemic bioavailability of desmethylastemizole was also increased. The QTc interval did not increase after astemizole administration and there was no difference in the QTc intervals between the itraconazole and placebo session. CONCLUSIONS: Chronic administration of itraconazole influences the metabolism of single dose astemizole in normal volunteers without changes of cardiac repolarization during the first 24 h after astemizole administration. However, the reduction in astemizole clearance under concomitant administration of itraconazole may result in a marked increase in astemizole plasma concentrations and QTc alterations during chronic combined intake of astemizole with itraconazole.

Administration, Oral↗

PubMed1994

The effect of activated charcoal on the absorption and elimination of astemizole.

1. The effect of activated charcoal on the absorption and elimination of astemizole and its metabolites was studied in healthy volunteers. 2. Subjects were divided into three groups containing seven subjects each. One group received 30 mg of astemizole with water only (control) and another group with 25 g of activated charcoal. The third group received multiple doses (12 g) of charcoal from 6 h onwards twice daily for 8 days. The concentrations of astemizole and its metabolites in plasma were measured by radioimmunoassay for 192 h. 3. Activated charcoal, administered immediately after astemizole ingestion, reduced the absorption of astemizole by 85% (P < 0.001). Multiple doses of activated charcoal, administered throughout the period of astemizole elimination, had no significant effect on the rate of elimination or the area under the curve from 0 to 192 h. 4. The absorption of astemizole from the gastrointestinal tract can be effectively prevented with activated charcoal. Because astemizole is rapidly absorbed, charcoal should be administered as soon as possible in acute astemizole poisoning. Multiple doses of charcoal do not seem to shorten the elimination half-life of astemizole.

Adult↗

PubMed1997

Effects of nonsedating antihistamine, astemizole, on the in situ canine heart assessed by cardiohemodynamic and monophasic action potential monitoring.

The possible mechanisms of cardiac adverse effects of astemizole were studied using a halothane-anesthetized in vivo canine model under the cardiohemodynamic and monophasic action potential monitoring. A dose of 0.3 mg/kg of iv astemizole (n = 7), which is close to the recommended dose for clinical use, showed a bradycardic effect and a reversed use-dependent lengthening of repolarization. The increase in the repolarization was greater than in the effective refractory period. These effects persisted even when the plasma drug concentration became undetectable. Additional administration of 3.0 mg/kg of iv astemizole (n = 7) decreased the mean blood pressure, suppressed the cardiac contraction and conduction, and induced early after depolarization-like potential in addition to the qualitatively similar effects compared to those observed by the lower dose. The decrease of the plasma concentration of astemizole followed the pattern predicted by the two-compartment theory of pharmacokinetics, but the drug concentration in the cardiac muscle was estimated to be more than 100 times greater than that in plasma. Our study emphasizes that each cardiac consequence of astemizole overdose may be related to proarrhythmic effects and the monitoring of plasma drug concentration will be less helpful in predicting the cardiac adverse effects of astemizole. The results provide some insights into the clinical cardiotoxicity of astemizole. Drugs or interventions inducing positive chronotropic, inotropic, and dromotropic effects can become good candidates for the treatment of astemizole intoxication, which may attenuate the cardiac effects of astemizole including the lengthening of repolarization.

Action Potentials↗

PubMed1987

Uptake, subcellular distribution and biotransformation of 3H-labelled astemizole in cultured rat hepatocytes.

When incubated with 3H-astemizole, a potent antagonist of H1 receptor, cultured rat hepatocytes, which do not express specific receptors for this ligand, avidly take up 3H-label proportionally to the drug concentration. HPLC analysis indicates that at 10 ng 3H-astemizole/ml, cells almost entirely deplete the culture medium of the drug within 4 hr of incubation. At 37 degrees, astemizole is metabolized and released into the culture medium mainly under the form of glucuronoconjugated metabolites. Differential centrifugation of homogenates from hepatocytes incubated with 3H-astemizole indicates that astemizole and unconjugated metabolites are found in the particulate fraction, whereas astemizole and conjugated metabolites are present in the cytosol. Isopycnic centrifugation on sucrose gradient shows that the major part of the 3H-label in the particulate fraction distributes like phospholipids and NADPH cytochrome c reductase, suggesting an association with membranes and, in particular, with the endoplasmic reticulum. Chloroquine, a drug accumulating within lysosomes and acidic endosomes, decreases the uptake of 3H-astemizole by hepatocytes and induces, during isopycnic centrifugation of a particulate fraction, a shift of the 3H-label towards lower densities where it closely accompanies cathepsin B. This suggests that a minor part of astemizole accumulated in the hepatocytes could be trapped within lysosomes. These results could support the hypothesis that aspecific binding of astemizole to cellular membranes and, to a lesser extent, trapping in lysosomes could play a role in the pharmacokinetics of the drug.

Animals↗

PubMed1996

Tilarin in combination with astemizole.

This multicentre double-blind, placebo controlled study had a practical objective, based on the expectation that many patients with seasonal allergic rhinitis will be prescribed oral antihistamine monotherapy by their primary care physician, whereas allergy specialists are more likely to prescribe combination therapy including antiinflammatories. The specific question was, "Will the addition of nedocromil sodium 1% nasal spray to astemizole tablets improve control of symptoms of seasonal allergic rhinitis induced by ragweed pollen, as compared to astemizole therapy alone?'. Following a one-week baseline, planned to coincide with the start of the local ragweed pollen season, patients (aged 12-64) were randomly assigned to four weeks' double-blind test treatment with either nedocromil sodium 1% nasal spray four times daily (QID) + astemizole (n = 146) or placebo nasal spray + astemizole (n = 148) or double-dummy (nasal spray + capsules) placebo (n = 71). Patient diary cards were kept throughout the five weeks, and clinic visits were made before and after baseline and after one and four weeks' treatment. During the 10-day peak pollen period, the diary card rhinitis symptom summary score (0-4 severity scale) was significantly reduced in patients receiving either astemizole alone (p < 0.001) or the combination therapy (p < 0.001) as compared with placebo. Direct comparison of the active treatments further showed that symptoms were significantly less severe (p < 0.01) with the combined therapy than with astemizole alone, and this despite significantly greater reliance on permitted rescue medications (p < 0.05 for pseudoephedrine usage) in the astemizole group. Clinical assessments of rhinitis made during the peak pollen visit, after the first week of test treatment, were also significantly (p < 0.05 - p < 0.01) in favour of combined therapy with nedocromil sodium 1% nasal spray + astemizole rather than astemizole alone, and at the same time this preference was confirmed by physician (p = 0.011) and patient (p = 0.003) opinions of symptom control. In conclusion, this antiinflammatory + antihistamine treatment proved superior to antihistamine alone for effective management of allergic rhinitis. The combined therapy worked quickly and was well-tolerated, with no serious adverse events or untoward effects on blood or urine variables.

Administration, Intranasal↗

PubMed1999

Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole.

INTRODUCTION: The selective H1-receptor antagonist astemizole (Hismanal) causes acquired long QT syndrome. Astemizole blocks the rapidly activating delayed rectifier K+ current I(Kr) and the human ether-a go-go-related gene (HERG) K+ channels that underlie it. Astemizole also is rapidly metabolized. The principal metabolite is desmethylastemizole, which retains H1-receptor antagonist properties, has a long elimination time of 9 to 13 days, and its steady-state serum concentration exceeds that of astemizole by more than 30-fold. A second metabolite is norastemizole, which appears in serum in low concentrations following astemizole ingestion and has undergone development as a new antihistamine drug. Our objective in the present work was to study the effects of desmethylastemizole, norastemizole, and astemizole on HERG K+ channels. METHODS AND RESULTS: HERG channels were expressed in a mammalian (HEK 293) cell line and studied using the patch clamp technique. Desmethylastemizole and astemizole blocked HERG current with similar concentration dependence (half-maximal block of 1.0 and 0.9 nM, respectively) and block was use dependent. Norastemizole also blocked HERG current; however, block was incomplete and required higher drug concentrations (half-maximal block of 27.7 nM). CONCLUSIONS: Desmethylastemizole and astemizole cause equipotent block of HERG channels, and these are among the most potent HERG channel antagonists yet studied. Because desmethylastemizole becomes the dominant compound in serum, these findings support the postulate that it becomes the principal cause of long QT syndrome observed in patients following astemizole ingestion. Norastemizole block of HERG channels is weaker; thus, the risk of producing ventricular arrhythmias may be lower. These findings underscore the potential roles of some H1-receptor antagonist metabolites as K+ channel antagonists.

Astemizole↗

PubMed1992

Pharmacokinetics of astemizole in children.

Astemizole is often administered to children in the treatment of rhinoconjunctivitis and urticaria with good efficacy and few side effects. Both astemizole and its major metabolite desmethylastemizole (DMA) are clinically effective without annoying side effects such as sedation. The pharmacokinetics in adults is well known. In three different studies we have investigated the pharmacokinetical properties of the drug in children. Study I (absorption): Thirty-eight children 8-16 years old (mean 12.6 years) and weighing 25-80 kg (mean 45 kg), with rhinoconjunctivitis due to birch pollinosis, were pretreated with either astemizole 5 mg daily or placebo for two weeks. Then, all children were treated with astemizole in doses increasing every week, i.e. 5, 10, 20 and 40 mg per day. There was a good correlation between the given dose per kg body weight and the plasma concentration of astemizole plus hydroxylated metabolites, indicating that astemizole is completely absorbed. Study II (time to reach steady state): A group of 21 children 7-18 years old (mean 13.9 years), plus 2 younger children, 2 and 5 years old, with allergy against birch- or grass pollen were treated with astemizole 10 mg daily for 12 weeks. Astemizole had reached steady-state plasma levels when the first sample was taken after 1 week, DMA reached steady state within 4 weeks. Study III (elimination half-life [t1/2 beta]): In 10 of the children from study II, t1/2 beta for astemizole plus DMA could be calculated (two samples) and was 10.8 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1986

The treatment of mild to severe chronic idiopathic urticaria with astemizole: double-blind and open trials.

Astemizole is a new H1 histamine-receptor antagonist that has a long elimination half-life and high H1-receptor affinity. This double-blind study evaluated the safety and efficacy of astemizole in the treatment of chronic idiopathic urticaria (more than or equal to 3 months). Seventeen male and 34 female adult patients with chronic idiopathic urticaria entered the 2-month study. After a 48- to 72-hour washout, half the subjects were prerandomized to receive astemizole (10 mg), and the other half received placebo. Placebo-treated patients who were unable to complete the full 8 weeks because of uncontrolled chronic urticaria symptoms were entered into a 2-month open astemizole trial. Treatment with astemizole, as measured at the end point of each patient's treatment and compared to placebo, resulted in significant improvement of pruritus, erythema, number of wheals, frequency of urticarial attacks, and control of urticaria (p less than or equal to 0.03). The overall response to astemizole was significantly better than for placebo, according to both the investigator's and the patient's global evaluations (p less than 0.01) and as indicated by dropouts caused by treatment failure with placebo (p = 0.005). Six of 26 (24%) of the placebo-treated patients in the double-blind study had good to excellent results on the basis of global assessments. Thirteen of 16 patients with placebo-treatment failures who received astemizole in the open trial improved significantly from baseline symptoms of pruritus, erythema, and number of wheals (p less than or equal to 0.05). No significant side effects were reported except mild sedation in three astemizole-treated subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1999

Electrophysiological effects of cetirizine, astemizole and D-sotalol in a canine model of long QT syndrome.

Observations of torsades de pointes during therapy with terfenadine and astemizole has raised concern about the cardiac safety of non-sedating H1-antagonist agents. We compared cetirizine, another compound of that class, to D-sotalol and to astemizole in a model of acquired long QT syndrome. Open-chest surgery was performed in adult beagle dogs anaesthetized with halothane and thiopental. Bradycardia was produced with beta-adrenergic blockade and sinus node crush. Four left ventricular intramyocardial unipolar monophasic action potentials (MAP) were recorded during atrial pacing at basic cycle lengths (BCL) 400-1500 msec, before and during three successive 1-h drug infusions (0.14, 0.45 and 1.4 mg/kg/h for astemizole and cetirizine and 1.1, 2.2 and 4.5 mg/kg/h for D-sotalol). Dose- and bradycardia-dependent prolongations of MAP duration (MAPD) were produced by D-sotalol (P < 0.001) and astemizole (P < 0.001) but not by cetirizine. At BCL 1500 ms, the three infusions of astemizole prolonged endocardial MAPD from 323 +/- 8 msec (mean +/- SE) at baseline to 343 +/- 10, 379 +/- 13 and 468 +/- 26 msec, respectively (n = 9). Sotalol prolonged that MAPD from 339 +/- 6 msec to 377 +/- 7, 444 +/- 15 and 485 +/- 24 msec (n = 7). In contrast, cetirizine did not prolong MAPD: 341 +/- 8 msec at baseline Vs 330 +/- 8, 324 +/- 9 and 323 +/- 11 msec (n = 9). Drug-induced increase in transmural dispersion reached +79 +/- 19 msec after astemizole, +59 +/- 21 msec after D-sotalol and only +7 +/- 11 msec after cetirizine. Runs of ventricular tachycardias and torsades de pointes occurred during dose three of astemizole (5/9 dogs) and D-sotalol (4/7 dogs) but never during cetirizine. In the present model, astemizole and D-sotalol but not cetirizine prolonged MAPD and transmural dispersions of repolarization and produced torsades de pointes. These results suggest that the halothane-anaesthetized bradycardic dog could be a valuable model to discriminate drugs for their class III effects and proarrhythmic potencies.

Action Potentials↗

PubMed2003

In vitro inhibition of human small intestinal and liver microsomal astemizole O-demethylation: different contribution of CYP2J2 in the small intestine and liver.

1. The effects of chemical agents on the metabolism of the antihistamine drug astemizole were investigated to evaluate drug-drug interactions. 2. 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. 3. 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. 4. 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. 5. 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.

Animals↗

PubMed1997

Effects of magnesium sulfate on the canine cardiovascular system complicating astemizole overdose.

Polymorphic ventricular arrhythmias induced by astemizole overdose have been reported to be successfully managed with intravenous magnesium sulfate. This study was designed to assess the effects of magnesium sulfate on the cardiovascular system, complicating astemizole overdose, the better to understand the therapeutic utility and undesirable effects of magnesium sulfate. Beagle dogs were anesthetized with halothane inhalation (n = 6). Monophasic action potential of the right ventricle, electrocardiogram, and systemic and left ventricular pressure were continuously monitored. Cardiac output was measured by a thermodilution method. Effective refractory period of the right ventricle was assessed by programmed electrical stimulation. An intentionally high dose of astemizole (3 mg/kg, i.v.) prolonged the repolarization and refractory period, while it decreased the sinus automaticity, ventricular contraction, and conduction. A canine antiarrhythmic dose of magnesium sulfate (100 mg/kg, i.v.) was additionally injected 1 h after i.v. astemizole. Magnesium sulfate increased the atrioventricular conduction time, electrical vulnerability, and preload of the left ventricle, while it decreased the blood pressure and cardiac output, besides the effects similar to those observed after i.v. astemizole. The plasma concentration of astemizole was at least 10 times higher than its therapeutic concentration during the experimental period. Magnesium sulfate could be expected to act as a calcium channel blocker during astemizole overdose; however, it may not antagonize the proarrhythmic effects of astemizole.

Animals↗

PubMed1998

Effects of astemizole on ventricular activation, effective refractory periods, RT intervals, and programmed stimulation-induced ventricular arrhythmias in dog hearts with myocardial infarction.

To clarify the mechanisms of enhanced cardiotoxic effects of astemizole in ischemic hearts, we examined the effects of astemizole on ventricular activation, effective refractory periods (ERPs), RT intervals, and incidence of programmed electrical stimulation (PES)-induced ventricular arrhythmias in the dog heart after myocardial infarction. Myocardial infarction was produced by the two-stage ligation of left anterior descending coronary artery in dogs. At 7 days after ligation, bipolar electrodes were sutured on the ventricular surface of the infarcted and the normal zones for applying an electrical stimulation or recording the ventricular activation. Ventricular-activation delay was measured in a premature excitation, which was produced by a stimulation at a coupling interval between 300 and 140 ms on the ventricular surface of the normal zone. The ERP and the RT interval were determined during atrial pacing. The ventricular-activation delay increased after astemizole at doses of 0.3-3 mg/kg in the infarcted zone and at 3 mg/kg in the normal zone. Astemizole at doses of 0.3-3 mg/kg significantly prolonged the ERP to a greater extent in the infarcted zone than in the normal zone, and thus a dispersion of ERP between normal and infarcted zones increased. The RT interval in the normal zone significantly increased after astemizole to a greater extent at a long coupling interval. The RT interval in the infarcted zone also increased after astemizole at doses of 0.1-3 mg/kg to a greater extent than that in the normal zone. Astemizole at doses of 0.3-3 mg/kg increased the incidence of PES-induced ventricular arrhythmias. In conclusion, enhanced cardiotoxic effects of astemizole in ischemic hearts may be caused by increased activation delay in the ischemic regions and increased ERP dispersion in the ventricle.

Animals↗

PubMed2001

Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine.

AIMS: The aims of the present study were to investigate the metabolism of astemizole in human liver microsomes, to assess possible pharmacokinetic drug-interactions with astemizole and to compare its metabolism with terfenadine, a typical H1 receptor antagonist known to be metabolized predominantly by CYP3A4. METHODS: Astemizole or terfenadine were incubated with human liver microsomes or recombinant cytochromes P450 in the absence or presence of chemical inhibitors and antibodies. RESULTS: Troleandomycin, a CYP3A4 inhibitor, markedly reduced the oxidation of terfenadine (26% of controls) in human liver microsomes, but showed only a marginal inhibition on the oxidation of astemizole (81% of controls). Three metabolites of astemizole were detected in a 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 catalysed 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. CONCLUSIONS: In contrast to terfenadine, a minor role for CYP3A4 and involvement of multiple P450 isozymes are suggested in the metabolism of astemizole. These differences in P450 isozymes involved in the metabolism of astemizole and terfenadine may associate with distinct pharmacokinetic influences observed with coadministration of drugs metabolized by CYP3A4.

Anti-Allergic Agents↗

PubMed2002

Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, astemizole.

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. Therefore, CYP2J2 cDNA has been isolated from the human cDNA library and expressed in COS-1 cells. A clear activity of astemizole O-demethylation was detected in recombinant CYP2J2 with K(m) = 0.65 microM and V(max) = 1129 pmol/nmol P450/min. Expression of the immunoreactive protein with CYP2J2 antibody was detected in the small intestine and liver. Expression levels of the immunoreactive protein with the CYP2J2 antibody in the small intestine were well correlated with the activities of the astemizole O-demethylation (r = 0.901, n = 5, p < 0.05). The CYP2J2 substrates, arachidonic acid and ebastine, strongly inhibited the microsomal astemizole O-demethylation in the human small intestines and recombinant CYP2J2. These results indicate the involvement of CYP2J2 in the presystemic elimination of astemizole in the human small intestine.

Animals↗

PubMed1997

Effects of the anti-allergics astemizole and norastemizole on Fc epsilon RI receptor-mediated signal transduction processes.

The non-sedating anti-allergic drug astemizole, apart from its potential to antagonise H1 receptors, inhibits the release of inflammation mediators from mast cells. To study the mechanism of this inhibition, we investigated the effects of astemizole and one of its active metabolites, norastemizole, on different phases of Fc epsilon RI (the high affinity receptor for the immunoglobulin IgE) receptor-activated signal transduction in rat basophilic leukemia cells (RBL-2H3), leading to exocytosis. Cells were stimulated either through antigen, or thapsigargin, or synergistic combinations of Fc epsilon RI receptor activation with either adenosine A3 receptors or integrins, activated by fibronectin adherence. The effects of the drugs on mediator release, inositol 1,4,5-trisphosphate formation, tyrosine phosphorylation of cellular proteins and Ca2+ fluxes were investigated. Inositol 1,4,5-trisphosphate levels are not affected. Astemizole increased tyrosine phosphorylation in resting cells, especially a 96-kDa protein band. Particularly tyrosine phosphorylation related to post Ca2+ processes is changed after cell triggering in the presence of astemizole. Both drugs inhibit the influx of 45Ca2+, with similar dose response curves as for the inhibition of exocytosis. Astemizole but not norastemizole, when used in resting cells, released Ca2+ from intracellular stores. Astemizole (> 15 microM) also induced exocytosis in resting cells. It did not induce additional changes in its inhibiting effect when cells were triggered with synergistic combinations of Fc epsilon RI receptor activation with either adenosine A3 receptors or integrins. Effects on haemolysis of erythrocytes and differential scanning calorimetry in liposomes showed clear differences in membrane perturbation between astemizole and norastemizole. The observed differences, and the role of membrane perturbation in the action on Ca2+ fluxes, are discussed.

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