Quantitative pharmacological analyses of the interaction between flumazenil and midazolam in monkeys discriminating midazolam: Determination of the functional half life of flumazenil

Abstract The duration of action of a drug is commonly estimated using plasma concentration, which is not always practical to obtain or an accurate estimate of functional half life. For example, flumazenil is used clinically to reverse the effects of benzodiazepines like midazolam; however, its elimination can be altered by other drugs, including some benzodiazepines, thereby altering its half life. This study used Schild analyses to characterize antagonism of midazolam by flumazenil and determine the functional half life of flumazenil. Four monkeys discriminated 0.178 mg/kg midazolam while responding under a fixed-ratio 10 schedule of stimulus-shock termination; flumazenil was given at various times before determination of a midazolam dose–effect curve. There was a time-related decrease in the magnitude of shift of the midazolam dose–effect curve as the interval between flumazenil and midazolam increased. The potency of flumazenil, estimated by apparent pA 2 values (95% CI), was 7.30 (7.12, 7.49), 7.17 (7.03, 7.31), 6.91 (6.72, 7.10) and 6.80 (6.67, 6.92) at 15, 30, 60 and 120 min after flumazenil administration, respectively. The functional half life of flumazenil, derived from potency estimates, was 57±13 min. Thus, increasing the interval between flumazenil and midazolam causes orderly decreases in flumazenil potency; however, across a broad range of conditions, the qualitative nature of the interaction does not change, as indicated by slopes of Schild plots at all time points that are not different from unity. Differences in potency of flumazenil are therefore due to elimination of flumazenil and not due to pharmacodynamic changes over time.