Biotransformation of the peripherally acting H-1 histamine antagonist, terfenadine, to its desalkyl and hydroxy metabolites was studied in vitro using microsomal preparations from six separate human livers. These metabolic reactions are mediated by the specific cytochrome P450-3A4. Addition of ketoconazole to the reaction mixtures reduced the rate of formation of both metabolites in a manner consistent with competitive inhibition. Ketoconazole inhibition constants (Ki) averaged 0.024 microM for the desalkyl terfenadine pathway, and 0.237 microM for the hydroxy terfenadine pathway. A mathematical model, based on the in vitro Ki values and the usual clinical range of plasma ketoconazole concentrations (1-5 micrograms/mL; 1.88-0.94 microM), predicted that plasma terfenadine levels during coadministration of ketoconazole would increase by a factor ranging from 13-fold to 59-fold relative to the same dose of terfenadine given without ketoconazole. Actual plasma terfenadine levels during terfenadine-ketoconazole coadministration in a clinical pharmacokinetic study were close to those predicted by the model. These plasma levels were associated with prolongation of the corrected QT interval, thereby explaining the potentially life-threatening ventricular arrhythmias reportedly associated with terfenadine-ketoconazole cotherapy. Thus, data from studies of drug metabolism in vitro can be used to predict and thereby possibly avoid clinically important drug interactions.