Vol. 285, Issue 1, 271-276, April 1998

Effects of Ketoconazole on Triazolam Pharmacokinetics, Pharmacodynamics and Benzodiazepine Receptor Binding in Mice¹

Jeanne M. Fahey, Gary A. Pritchard, Lisa L. von Moltke, John S. Pratt, Jeffrey M. Grassi, Richard I. Shader and David J. Greenblatt

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and the Division of Clinical Pharmacology, New England Medical Center, Boston, Massachusetts.

We previously demonstrated that ketoconazole is a potent inhibitor of triazolam biotransformation in vitro and in vivo. Despite significant elevations in triazolam plasma levels with coadministration of ketoconazole, the pharmacodynamic enhancement was lower than predicted based on plasma levels of triazolam. The present study examines the effects of ketoconazole on benzodiazepine receptor binding in vitro as well as on open-field behavior in male CD-1 mice. Triazolam alone inhibited [³H]flunitrazepam binding with an IC₅₀ value of 0.85 nM and a K_i value of 0.50 nM. Ketoconazole alone also competitively antagonized [³H]flunitrazepam binding in a concentration-dependent manner with an IC₅₀ value of 1.56 µM and a K_i value of 1.17 µM. In the presence of 1, 3 or 9 µM ketoconazole, the IC₅₀ value of triazolam was increased to 1.11, 1.58 and 5.73 nM, respectively, whereas maximal binding was reduced by 36%, 69% and 89%. Coadministration of 50 mg/kg ketoconazole and triazolam (0.1-0.3 mg/kg) to intact animals significantly elevated plasma and brain triazolam levels. Ketoconazole could be measured in mouse brain at levels averaging 31% of those in plasma. Ketoconazole alone had minimal or no effect on open field activity, but it significantly potentiated the decreased activity seen with triazolam administration. The ability of ketoconazole to inhibit triazolam displacement of [³H]flunitrazepam binding may explain the muted pharmacodynamic effect of this benzodiazepine in the presence of ketoconazole. Based on these results, it is likely that ketoconazole acts as a neutral ligand at the benzodiazepine receptor.