Ketoconazole-terfenadine interaction

Terfenadine is at least 70% absorbed after oral administration but is rapidly metabolized by first-pass metabolism to fexofenadine (terfenadine carboxylate) and an inactive dealkylated product. Metabolism appears to be mediated entirely by the CYP (CYP3A4). Fexofenadine is about 70% protein bound and exhibits biphasic elimination with an initial plasma half-life of 3.5 hours and a terminal plasma half-life of 6 to 12 hours. Fexofenadine is excreted mostly unchanged (80% in feces, 12% in urine), with <10% converted to inactive metabolites (7). Fexofenadine excretion can be affected by compounds (e.g., ketoconazole) that interact with the P-glycoprotein transporter because fexofenadine is a substrate for this transporter (8). 

Jurima-Romet, M. Crawford, K. Cyr, T. Inaba, T. Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals. Drug Metab.Dispos., 1994, 22, 849—857 [extracted metabolites microsomal incubations rat column temp 35 LOQ 92 nM] von Moltke, L.L. Greenblatt, D.J. Duan, S.X. Harmatz, J.S. Shader, R.I. In vitro prediction of the terfenadine-ketoconazole pharmacokinetic interaction. J.Clin.Pharmacol., 1994, 34, 1222—1227 [clomipramine (IS) microsomal incubations]... 

Honig PK, Wortham DC, Zamani K, et al. Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. JAMA 1993 269 1513-1518. 

SSRIs TERFENADINE Possibility oft plasma concentrations of these drugs and potential risk of dangerous arrhythmias These drugs are metabolized mainly by CYP3A4. Fluvoxamine and fluoxetine are inhibitors of CYP3A4 but are relatively weak compared with ketoconazole, which is possibly 100 times more potent as an inhibitor The interaction is unlikely to be of clinical significance but need to be aware... 

Interactions. Drugs that lower gastric acidity, e.g. antacids, histamine H2 receptor antagonists, impair the absorption of ketoconazole from the gastrointestinal tract. Like all imidazoles, ketoconazole binds strongly to several cytochrome P450 isoenzymes and thus inhibits the metabolism (and increases effects of) oral anticoagulants, phenytoin and cyclosporin, and increases the risk of cardiac arrhythmias with terfenadine. A disulfiram-like reaction occurs with alcohol. Concurrent use of rifampicin, by enzyme induction of CYP 3A, markedly reduces the plasma concentration of ketoconazole. 

Terfenadine can cause prolongation of the QT interval in overdose or during interactions with drugs that inhibit its metaboUsm, such as erythromycin (1), ketoconazole (2), and grapefruit juice (3). Torsade de pointes can result (4). 

Terfenadine can cause prolongation of the QT interval in overdose or during interactions with drugs that inhibit its metaboUsm, such as ketoconazole. 

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