Astemizole pharmacokinetics

Several nonsedative Hj inhibitors have been marketed—for example, astemizole (4.149) and terfenadine (4.150). They are quite polar molecules and therefore cannot cross the blood-brain barrier to reach central histamine receptors. This is a good example of drug design exploiting knowledge of the pharmacokinetic processes to preclude undesirable CNS side effects. 

The pharmacokinetics of saquinavir is modified by agents that alter isoenzyme CYP3A4 of the cytochrome P-450 system and P-glycoprotein transporter. It should not be administered with midazolam, triazolam and ergot derivatives. The plasma concentrations of saquinavir are lower when coadministered with efavirenz, nevirapine or rifampin. Ritonavir reverses the effects of nevirapine on saquinavir. The coadministration of astemizole, terfenadine, amiodarone, bepridil, quinidine, propafenone or flecainide with saquinavir is also not recommended due to its potential for serious and/or life-threatening reactions. 

Lefebvre RA, Van Peer A, Woestenborghs R. Influence of itraconazole on the pharmacokinetics and electrocardiographic effects of astemizole. Br J Clin Pharmacol 1997 43(3) 319-22. 

Toxic effects of terfenadine and astemizole have been reported in patients taking concomitant macrohdes, especially clarithromycin (87-89,116), typically resnlting in prolongation of the QT interval and cardiac dysrhjdhmias (torsade de pointes) (111). The potential interaction of azithromycin with terfenadine has been evaluated in a randomized, placebo-controlled study in 24 patients who took terfenadine plus azithromycin or terfenadine pins placebo (90). However, azithromycin did not alter the pharmacokinetics of the active carboxylate metabolite of terfenadine or the effect of terfenadine on the QTc interval. 

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. 

In vitro studies have shown that ketoconazole inhibits the metabolism of astemizole. Ketoconazole, and to a lesser extent itraconazole and miconazole, also appear to reduce the metabolism of terfenadine by inhibition of the cytochrome P450 isoenzyme CYP3A. " High serum levels of astemizole and terfenadine (but not its metabolites) block cardiac potassium channels leading to prolongation of the QT interval, which may precipitate the development of torsade de pointes arrhythmia (see Table 15.2 , (p.583)). The risk of cardiac arrhythmias with other non-sedating antihistamines appears to be non-existent or very much lower (see Table 15.2 , (p.583)), so any pharmacokinetic interactions do not result in clinically relevant cardiac toxicity. In fact, studies have shown that desloratadine at nine times the recommended dose, fexofenadine in overdose, and mizolastine at four times the recommended dose do not affect the QT interval. However, some questions remain about loratadine and ebastine. Additionally, some studies have reported that ketoconazole alone is associated with a small increase in QT interval, and at least one case of torsade de pointes has been reported for ketoconazole alone. Therefore the cardiac effects of ketoconazole may be additive with those of the antihistamines, and this may be important for ebastine and loratadine. 

Grapefruit juice raises terfenadine ievels, increasing the risk of QT interval prolongation and torsade de pointes arrhythmias. Grapefruit juice does not appear to alter the pharmacokinetics of astemizole and desloratadine. The absorption of fexofenadine is modestly reduced by grapefruit juice, orange juice and apple juice. 

In a study in 12 healthy subjects the steady-state pharmacokinetics of astemizole (30 mg daily ford days, then 10 mg daily for the next 20 days), were unaffected by 800 mL of grapefruit juice (given as 200 mL every... 

Astemizole 30 mg daily for 4 days followed by 10 mg daily for the next 20 days, was given to 12 healthy subjects. The steady-state pharmacokinetics of the astemizole were then examined after the subjects took quinine 20 mg every 4 hours for 12 hours (a total of 80 mg quinine), and after a single 430-mg dose of quinine. The smaller dose of quinine caused only a slight increase in the maximum plasma astemizole levels and AUC, but the larger single dose of quinine resulted in a transient threefold increase in both maximum plasma levels and AUC, especially of desmethylastem-izole, the metabolite of astemizole. ... 

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