QT-prolongation effect of orally administered terfenadine in conscious cynomolgus monkeys: Interaction with ketoconazole
2005
Ando, K.(Mitsubishi Chemical Safety Inst., Kamisu, Ibaraki (Japan). Kashima Lab.) | Unakami, S. | Obo, M. | Sakai, A. | Makita, Y. | Yamamoto, Y. | Hayashi, K.
The present study examined whether the effects of terfenadine administered via the clinical route on the electrocardiographic QT interval could be captured in an animal experiment using cynomolgus monkeys. Further, we also investigated any possible effect on hERG (human ether-a-go-go-related gene) potassium current at the plasma concentration when terfenadine caused QT interval prolongation. No effects were found on the corrected QT interval (QTc) in the monkeys when terfenadine alone was administered at 10 to 100 mg/kg. When pretreated with ketoconazole (100 mg/kg), a CYP3A4 inhibitor, terfenadine was administered at the pharmacologically effective dose of 30 mg/kg prolonged QTc. The Cmax value of terfenadine at this time was 26.1 ng/mL (about 50 nmol/L). hERG potassium currents were significantly blocked at 1 nmol/L, corresponding to 2% of terfenadine at 50 nmol/L. From the results that terfenadine prolonged QTC in cynomolgus monkeys when administered via the clinical route with pretreatment with ketoconazole and that 1 nmol/L blocked hERG potassium current, it is suggested that the present in vivo and in vitro methods may be useful in predicting QT prolongation effects in humans.
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