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...

Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.

The objective of this investigation was to characterize quantitatively the pharmacodynamic interaction between N-[2-[4-(2-The 8-OH-DPATinduced change in body temperature was used as a pharmacodynamic endpoint. Four groups of rats each received 1 mg/kg 8-OH-DPAT in 5 min during computer-controlled infusions of physiological saline or WAY-100,635, targeted at steady-state concentrations of 20, 85, and 170 ng/ml. Body temperature was monitored continuously with a telemetric system, and frequent blood samples were obtained to determine the pharmacokinetics of both drugs. Large differences in pharmacokinetics were observed between WAY-100,635 and R-8-OH-DPAT, reflected in values of the terminal elimination half-life of 33 and 143 min, respectively. Infusion of WAY-100,635 had no influence on the pharmacokinetics of R-8-OH-DPAT. With regard to the pharmacodynamics, clear antagonism of the R-8-OH-DPAT-induced hypothermia was observed. The complex pharmacological effect versus time profiles of R-8-OH-DPAT were analyzed on the basis of an indirect physiological response model with set point control coupled to a competitive interaction model for an agonist and antagonist acting at a common receptor. This model converged, yielding precise estimates of the pharmacodynamic parameters of both WAY-100,635 and R-8-OH-DPAT, which were independent of the infusion rate of WAY-100,635. The estimated in vivo binding constant of WAY-100,635 was 0.98 ng/ml (2.3 nM), which is very similar to the reported value from in vitro receptor binding assays. The findings of this investigation show that, in contrast to earlier reports in the literature, WAY 100,635 behaves as a pure competitive antagonist at the 5-hydroxytryptamine 1A receptor in vivo.Over the years, several, more or less, stable agonists at the 5-HT 1A receptor have been developed that differ in both affinity and intrinsic efficacy. Of these 5-HT 1A ligands,

The pharmacokinetics of flumazenil in the rat were determined after 2.5 mg/kg intravenous and 25 mg/kg oral administration. Following intravenous administration flumazenil was rapidly eliminated with an extremely short terminal half-life (mean +/- SE, n = 8) of 8.3 +/- 0.3 min due to a large total blood clearance of 147 +/- 7 ml/kg/min combined with a relatively small volume of distribution at steady-state of 1.33 +/- 0.07 l/kg. After oral administration flumazenil was rapidly absorbed; however, the bioavailability was low (28 +/- 4%) and variable. Flumazenil was found to be unstable in rat blood in vitro and disappeared with a half-life (mean +/- SE, n = 5) of 8.3 +/- 1 min and 31 +/- 4 min at body and room temperature, respectively. The blood samples were stabilized by addition of sodium fluoride (NaF) and cooling to 0 degrees C. The samples had to be stored at -35 degrees C when analyzed at later times. Presumably esterases in rat blood are responsible for the observed instability. A sensitive HPLC assay to measure flumazenil concentrations in small blood samples is also described.

The results show that current-dependent delivery of apomorphine is possible in vivo at acceptable levels of skin irritation. Excellent correlation was found between the calculated in vivo transport rates and the rates that were previously obtained in vitro.