Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam

Abstract

Purpose The effects of grapefruit juice (GJ) on benzodiazepine hypnotics, triazolam (metabolized by CYP3A4) and quazepam (metabolized by CYP3A4 and CYP2C) were determined in this study. Methods Nine healthy male subjects (genotyped as wild type CYP2C9) took triazolam 0.25mg or quazepam 15mg with or without GJ. The trial was performed by a randomized, cross-over design with an interval of more than 2 weeks. Blood was obtained after each dosing. Phrmacodynamic effects were determined by digit symbol substitution test (DSST). Results GJ increased plasma concentrations of triazolam, and quazepam and its active metabolite, 2-oxoquazepam. The AUC of triazolam significantly increased by 96%. The elevations of this parameter of quazepam (38%) and 2-oxoquazepam (28%) were not significant. Triazolam reduced the number of digit substitutions while the effect of quazepam on the DSST was negligible. GJ deteriorated the performance in the DSST at 2 h after dosing of triazolam (-11 digits, P<0.05), but not of quazepam. A significant correlation was observed between plasma triazolam concentration and the decrease in the number of digit substitutions at 2h after dosing (P<0.05). Conclusions These results suggest that the effects of GJ on the pharmacokinetics and pharmacodynamics of triazolam are greater than those of quazepam. These GJ-related different effects are partly explained by the fact that triazolam is metabolized by CYP3A4, and quazepam by CYP3A4 and CYP2C9. Clinical Pharmacology & Therapeutics (2004) 75, P29–P29; doi: 10.1016/j.clpt.2003.11.110