Mechanism-Based Modeling of the Pharmacodynamic Interaction of Alphaxalone and Midazolam in Rats

Abstract

The objective of the present investigation was to characterize the pharmacodynamic interaction between the synthetic neuroactive steroid alphaxalone and the benzodiazepine midazolam. The time course of the electroencephalographic (EEG) effect (11.5-30 Hz) was determined in rats in conjunction with plasma concentrations. Alphaxalone was administered as a continuous intravenous infusion of 0, 1.2, 2.2, or 5.2 mg over 360 min. Midazolam was administered as a 5-min intravenous bolus infusion of 4 mg⅐kg Ϫ1 . The pharmacokinetic profiles of both drugs were described by a two-compartment model. No pharmacokinetic interaction was observed. The EEG effect versus time profiles of midazolam and alphaxalone, when administered separately and in combination, were modeled on the basis of the recently proposed mechanism-based pharmacokinetic/pharmacodynamic model for GABA A receptor modulators, which contains separate expressions to describe the drug-receptor interaction and the stimulus-response relationship. The pharmacodynamic interaction between alphaxalone and midazolam was best characterized using an independent drug-drug interaction model without an expression for allosteric modulation of the effect of midazolam by alphaxalone. The final model contained an exponential expression to account for acute functional adaptation to the EEG effect upon continuous infusion of alphaxalone. The mechanism-based analysis showed that this functional adaptation is best explained by a change in the system-specific stimulus-response relationship, rather than the drug-receptor activation process. It is concluded that the pharmacodynamic interaction between alphaxalone and midazolam in vivo is best described using an independent interaction model without allosteric modulation.Recently, a mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model was developed for the electroencephalographic (EEG) effects of a wide array of GABA A receptor modulators, including neuroactive steroids, benzodiazepines, imidazopyridines, cyclopyrrolones, and ␤-carbolines (Visser et al., 2002a(Visser et al., ,b, 2003a. A unique feature of this model is that it contains separate expressions for the characterization of 1) the receptor activation process and 2) the signal-transduction process. In this specific model, the receptor activation process is described by a hyperbolic function, whereas the biphasic transducer function is described by a parabolic equation (Fig. 1). It has been shown that a single unique transducer function can describe the effects of the different GABA A modulators. In this paradigm, neuroactive steroids and benzodiazepines differ in their ability to activate the receptor. It has also been shown that the model can account for the additive effects upon activation of two distinct GABA A receptor subtypes by zolpidem in vivo (Visser et al., 2003b).The objective of the present investigation was to determine whether the mechanism-based PK/PD model could be used to characterize the effect of neuroactive steroids and benzodiazepines whe...

The Effect of Anesthesia and Surgery on Cyp3a Activity in Rats

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