MIDAZOLAM AND FLUMAZENIL PHARMACOKINETICS AND PHARMACODYNAMICS FOLLOWING SIMULTANEOUS ADMINISTRATION TO HUMAN VOLUNTEERS

Resedation after antagonism of midazolam sedation with flumazenil may occur because some individuals have rapid elimination of flumazenil bu t slow elimination of midazolam. To determine whether there are parall el or divergent rates of elimination of the two drugs between individu als, the pharmacokinetic profiles of midazolam and flumazenil were stu died simultaneously in 12 adult male volunteers. Free drug concentrati on data for the two drugs were incorporated into a receptor occupancy model and psychomotor testing was performed and correlated with recept or occupancy. Variation was found between individuals in the pharmacok inetics of the two drugs. There were significant correlations between Cl-tot (P < 0.01) but not in t(1/2 alpha), t(1/2 beta), V-c, or VDss. In individuals, midazolam elimination half-life ranged from less than half that of flumazenil to more than three times that of flumazenil. T here was a relatively poor, although statistically significant linear correlation found between calculated receptor occupancy and critical f licker fusion frequency, r = 0.50, P < 0.01, and linear analogue scale s of sedation r = 0.56, P < 0.005; and anxiolysis, r = 0.54, P < 0.005 . There is divergence in the disposition and elimination of midazolam and flumazenil in some individuals. A benzodiazepine receptor occupanc y model is useful for predicting the consequent differences in clinica l effect when the drugs are given together.