Astemizole metabolism

The manufacturer of astemizole contraindicates the concurrent use of SSRIs because there is a risk that they will inhibit astemizole metabolism, leading to a rise in its serum levels, which could result in QT interval prolongation and the development of torsade de pointes arrhythmias. ... 

Matsumoto S, Hirama T, Matsubara T, Nagata K, Yamazoe Y. 2002. Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, astemizole. Drug Metab... 

CYP3A4 is involved in the metabolism of 80%-90% of all currently available drugs (Table 2). Its presence accounts for the majority of the cytochrome enzymes in the liver. It has attracted attention from both physicians and pharmaceutical companies, as there have been incidences of fatal drug interactions, which have resulted in the withdrawal of these drugs from the market (terfena-dine in 1997, astemizole in 1999, and cisapride in 2000). Combinations ofpotent CYP3A4 inhibitors and substrates can drive drug levels to the toxic range. The... 

Patients with hepatic insufficiency may not tolerate the drug at usual doses, however, because of increased area under the concentration curve of both parent drugs and metabolites. This may necessitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg every 8 hours in some patients. Quinupristin and dalfopristin are not metabolized by cytochrome P450 enzymes but significantly inhibit CYP 3 A4, which metabolizes warfarin, diazepam, astemizole, terfenadine, cisapride, nonnucleo- side reverse transcriptase inhibitors, and cyclosporine, among others. Dosage reduction of cyclosporine may be necessary. 

Interactions Erythromycin and clarithromycin inhibit the hepatic metabolism of theophylline, warfarin, terfenadine, astemizole, carbamazepine and cyclosporine which can lead to toxic accumulations of these drugs. An interaction with digoxin may occur in some patients. In this case, the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin, thus leading to greater reabsorption of digoxin from the enterohepatic circulation. 

PROTEASE INHIBITORS ANTIHISTAMINES-ASTEMIZOLE, CHLORPHENAMINE, TERFENADINE Possibly t adverse effects with amprenavir, atazanavir, indinavir, ritonavir (with or without lopinavir), saquinavir and tipranavir Inhibition of CYP3A4-mediated metabolism of astemizole the risk is greatest in patients who are slow CYP2D6 metabolizers because chlorphenamine and terfenadine are also metabolized by this route Avoid co-administration... 

Astemizole is metabolized by CYP3A4 to desmethyl-astemizole and norastemizole, although these metabolites may not be free of the potential to prolong the QT interval. 

If erythromycin and ketoconazole, both CYP3A4 inhibitors, are taken in combination, there will be an even more dramatic effect on the metabolism of other drugs, such as terfenadine and astemizole, midazolam and triazolam, and ciclosporin. 

Mibefradil inhibits CYP3A4 (2). Other drugs that are metabolized by this pathway accumulate as a result. Drugs that were commonly affected included amiodarone, astemizole, ciclosporin, cisapride, erythromycin, imi-pramine, lovastatin, propafenone, quinidine, simvastatin (9), tacrohmus (10), tamoxifen, terfenadine, thioridazine, and drugs that impair sinoatrial node function (for example beta-blockers) (6). 

In general, itraconazole is more effective and better tolerated than is ketoconazole. Unlike ketoconazolc. it is not hep-atotoxic and does not cause adrenal or testicular suppression in recommended therapeutic doses.Nonetheless, itraconazole can inhibit cytochrome P-4S0 oxidases involved in drug and xenobiotic metabolism and is known to increase plasma levels of the aniihislaminic drugs terfenadine and astemizole. 

Astemizole undergoes extensive first-pass hepatic metabolism via cytochrome P450 (CYP 450) enzymes (primarily 3A4) to three primary, active, metabolites, desmethylastemizole, norastemizole, and 6-hydroxydesmethylastemizole. The major metabolites of astemizole, desmethylastemizole and norastemizole, possess antihistaminic activity approaching that of the parent compound. The of astemizole... 

Example Diphenhydramine HC1 (Benadryl), astemizole (Hismanal), cetirizine (Zyrtec) chlorpheniramine maleate (Chlor-Trimeton, Kolomnin, Phenetron, Techlor, Teldrin) loratadine (Claritin) Route PO, IM, IV Pregnancy category B Pharmacokinetic Absorbed from GI tract. Metabolized by the liver and excreted in urine. 

Drug-induced TdP has become an extremely visible hazard plaguing new drugs, sometimes resulting in public health disasters. For instance, cisapride, astemizole, and terfenadine are potent potassium channel blockers that were withdrawn from the market because of TdP. All these agents are metabolized rapidly to active moieties... 

CYP2J subfamily. CYP2J2 is the only gene of this subfamily. It is known to be expressed in many extrahepatic tissues and may play a role in the oxidative bioactivation of arachidonic acid to form epoxyeicosatrienoic acids, which modulate bronchial smooth muscle tone and airway transepithelial ion transport [53], CYP2J2 is also active toward other compounds such as linoleic acid and testosterone. Recently, it has been reported that CYP2J2 is involved in the intestinal first-pass metabolism of an antihistamine drug, astemizole [54],... 

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