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...

It has been shown that αMSH and the nonmelanotropic ACTH/MSH(4–9) analog ORG 2766 can ameliorate cisplatin-induced neurotoxicity and ototoxicity. Here, we investigated whether these peptides delay the occurrence of the cisplatin-induced shift in auditory threshold, and whether they affect the subsequent recovery of cochlear potentials. Chronically implanted round window electrodes were used to obtain daily recordings of auditory nerve compound action potentials (CAP) and cochlear microphonics at frequencies ranging from 2 to 16 kHz. Cisplatin (1.5 mg/kg i.p.) plus αMSH, ORG 2766 (75 µg/kg s.c.), or saline were injected daily until the 40-dB CAP threshold shift at 8 kHz was reached. Endocochlear potential (EP) was measured either 1–2 days or 28 days later, followed by morphometric analysis of the cochlea. Peptide cotreatment did not consistently delay the threshold shift; however, the CAP threshold recovered faster and to a greater extent, with the potency order being αMSH > ORG 2766 > saline. Significant recovery at the 2 highest frequencies was seen in the αMSH-treated animals only. CAP amplitude at high sound pressures, which depends more on nerve function than on outer hair cell (OHC) function, decreased severely in all groups but recovered significantly in the αMSH- and completely in the ORG-2766-cotreated group. EP was significantly lower in the first days after the threshold shift but had completely recovered at 28 days. Morphometric analysis of the spiral ganglion also indicated involvement of ganglion cells. OHC loss was most severe in the basal turn of saline-cotreated animals. These data suggest that the cisplatin-induced acute threshold shift might be due to reversible strial failure, whereas subsequent OHC survival determines the final degree of functional recovery. Both OHC loss and neuronal function were ameliorated by peptide cotreatment.

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...

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