EFFECTS OF KETOCONAZOLE ON TRIAZOLAM PHARMACOKINETICS, PHARMACODYNAMICS AND BENZODIAZEPINE RECEPTOR-BINDING IN MICE

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 ketocon azole, 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 [ H-3]flunitrazepam binding with an IC50 value of 0.85 nM and a K-i valu e of 0.50 nM, Ketoconazole alone also competitively antagonized [H-3]f lunitrazepam binding in a concentration-dependent manner with an IC50 value of 1.56 mu M and a K-i value of 1.17 mu M. In the presence of 1, 3 or 9 mu M ketoconazole, the IC50 value of triazolam was increased t o 1.11, 1.58 and 5.73 nM, respectively, whereas maximal binding was re duced by 36%, 69% and 89%. Coadministration of 50 mg/kg ketoconazole a nd triazolam (0.1-0.3 mg/kg) to intact animals significantly elevated plasma and brain triazolam levels. Ketoconazole could be measured in m ouse brain at levels averaging 31% of those in plasma. Ketoconazole al one had minimal or no effect on open field activity, but it significan tly potentiated the decreased activity seen with triazolam administrat ion. The ability of ketoconazole to inhibit triazolam displacement of [H-3]flunitrazepam binding may explain the muted pharmacodynamic effec t of this benzodiazepine in the presence of ketoconazole. Based on the se results, it is likely that ketoconazole acts as a neutral ligand at the benzodiazepine receptor.