Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA A Receptor in Vivo

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A mechanism-based pharmacokinetic-pharmacodynamic (PK/ PD) model for neuroactive steroids, comprising a separate characterization of 1) the receptor activation process and 2) the stimulus-response relationship, was applied to various nonsteroidal GABA A receptor modulators. The EEG effects of nine prototypical GABA A receptor modulators (six benzodiazepines, one imidazopyridine, one cyclopyrrolone, and one ␤-carboline) were determined in rats in conjunction with plasma concentrations. Population PK/PD modeling revealed monophasic concentration-EEG effect relationships with large differences in potency (EC 50 ) and intrinsic activity between the compounds. The data were analyzed on the basis of the mechanism-based PK/PD model for (synthetic) neuroactive steroids on the assumption of a single and unique stimulus-response relationship. The model converged yielding estimates of both the apparent in vivo receptor affinity (K PD ) and the in vivo intrinsic efficacy (e PD ). The values of K PD ranged from 0.41 Ϯ 0 ng⅐ml Ϫ1 for bretazenil to 436 Ϯ 72 ng⅐ml Ϫ1 for clobazam and the values for e PD from Ϫ0.27 Ϯ 0 for methyl 6,7-dimethoxy-4-ethyl-␤-carboline-3-carboxylate to 0.54 Ϯ 0.02 for diazepam. Significant linear correlations were observed between K PD for unbound concentrations and the affinity in an in vitro receptor bioassay (r ϭ 0.93) and between e PD and the GABA-shift in vitro (r ϭ 0.95). The findings of this investigation show that the in vivo effects of nonsteroidal GABA A receptor modulators and (synthetic) neuroactive steroids can be described on the basis of a single unique transducer function. In this paradigm, the nonsteroidal GABA A receptor modulators behave as partial agonists relative to neuroactive steroids.The pharmacokinetic-pharmacodynamic correlations of benzodiazepines have been the subject of numerous studies in both animals and humans for review, see Laurijssens and Greenblatt, 1996), but the predictive value of the proposed models seems to be limited. To date, there is an increasing interest in the development of mechanism-based PK/PD models because they allow the prediction of drug effects in vivo in a strict, quantitative manner on the basis of results obtained in in vitro test systems. These models not only provide a scientific basis for the prediction of drug effects in humans on the basis of results obtained in animal studies but also allow a mechanistic understanding for observed interindividual variability in drug response (Van der Graaf and Danhof, 1997).The need for mechanism-based modeling is illustrated by the difficulty of predicting the in vivo intrinsic activity of benzodiazepine receptor partial agonists in humans on the basis of results obtained in preclinical investigations. For example, in humans, the new benzodiazepine Ro 46-2153 behaved as a full agonist, whereas it was selected from preclinical studies based on its partial agonist properties (Goggin et al., 2000).In mechanism-based PK/PD models that are based on receptor theory, a separation is made between th...

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confidence: 99%

Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of the Electroencephalogram Effects of GABA_AReceptor Modulators: In Vitro-in Vivo Correlations

Visser¹,

Wolters²,

Gubbens‐Stibbe³

et al. 2003

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“…Previously (Visser et al, 2002b), it was also shown that a variation in baseline value (E 0 ) is reflected via the parameter a in the maximal achievable response in this system (E top ) according to the following.…”

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confidence: 99%

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

Visser¹,

Huntjens²,

Graaf³

et al. 2003

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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...

“…It was also shown that a variation in E 0 is reflected in the maximal achievable response in this system (E top ), via parameter a following Visser et al (2002b):…”

Section: Downloaded Frommentioning

confidence: 99%

“…In the present analysis, the parameters determining the shape of the stimulus-response relationship were fixed at values with the corresponding interindividual variability obtained previously; A ϭ 9.2 (22%), b ϭ 0.44 (7%), and d ϭ 3.36 (Ϫ), respectively (Visser et al, 2002b(Visser et al, , 2003. For the estimation of a one-site model versus the two-site model, the parameters ␣ 2 and e PD2 are fixed to zero in eqs.…”

Section: Subtype Selectivity Of Zolpidem In Vivo 1253mentioning

confidence: 99%

Dose-Dependent EEG Effects of Zolpidem Provide Evidence for GABA_AReceptor Subtype Selectivity in Vivo

Visser

Wolters²,

Graaf³

et al. 2002

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Zolpidem is a nonbenzodiazepine GABA A receptor modulator that binds in vitro with high affinity to GABA A receptors expressing ␣ 1 subunits but with relatively low affinity to receptors expressing ␣ 2 , ␣ 3 , and ␣ 5 subunits. In the present study, it was investigated whether this subtype selectivity could be detected and quantified in vivo. Three doses (1.25, 5, and 25 mg) of zolpidem were administered to rats in an intravenous infusion over 5 min. The time course of the plasma concentrations was determined in conjunction with the change in the ␤-frequency range of the EEG as pharmacodynamic endpoint. The concentration-effect relationship of the three doses showed a dosedependent maximum effect and a dose-dependent potency. The data were analyzed for one-or two-site binding using two pharmacodynamic models based on 1) the descriptive model and 2) a novel mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for GABA A receptor modulators that aims to separates drug-and system-specific properties, thereby allowing the estimation of in vivo affinity and efficacy. The application of two-site models significantly improved the fits compared with one-site models. Furthermore, in contrast to the descriptive model, the mechanism-based PK/PD model yielded dose-independent estimates for affinity (97 Ϯ 40 and 33,100 Ϯ 14,800 ng ⅐ ml Ϫ1 ). In conclusion, the mechanismbased PK/PD model is able to describe and explain the observed dose-dependent EEG effects of zolpidem and suggests the subtype selectivity of zolpidem in vivo.The GABA A receptor is a hetero-oligomeric protein consisting of five subunits that form an integral Cl Ϫ channel (for review, see Sieghart, 1995). To date, various GABA A receptor subunits and their isoforms (␣ 1 -␣ 6 , ␤ 1 -␤ 3 , ␥ 1 -␥ 3 , ␦, , ⑀, , and ) have been described (Barnard et al., 1998;Sieghart, 2000). In theory, these subunits can assemble to many GABA A receptor subtypes. In the central nervous system, however, functional GABA A receptors are formed mainly by combinations of ␣, ␤, and ␥ subunits (Barnard et al., 1998).According to a historical classification, benzodiazepines exert their anxiolytic/hypnotic actions through the activation of two pharmacologically distinct binding sites, 1 (BZ 1 ) and 2 (BZ 2 ), which were classified on the basis of differing affinities of CL 218.872 and zolpidem, respectively. In the meantime, it has been shown in in vitro investigations that zolpidem, which is a hypnotic of the imidazopyridine class, differs from conventional benzodiazepines (e.g., flunitrazepam and diazepam) and other hypnotics (zopiclone). Zolpidem displays high affinity at GABA A receptors expressing ␣ 1 subunits (K i ϭ 15-350 nM) but a relatively low affinity at receptors expressing ␣ 2 , ␣ 3 , and ␣ 5 subunits (K i ϭ 4 -40 M), whereas benzodiazepines have equal affinity for the various GABA A receptor subtypes (Pritchett et al., 1989;Ruano et al., 1992;Benavides et al., 1993;Luddens and Korpi, 1995). In addition, it has become clear that receptors with ␣ 1 subunits me...