Neuroactive steroids differ in potency but not in intrinsic efficacy at the GABA(A) receptor in vivo.

The objective of the present investigation was to characterize the in vivo EEG effects of (synthetic) neuroactive steroids on the basis of a recently proposed mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model. After intravenous administration, the time course of the EEG effect of pregnanolone, 2beta-3alpha-5alpha-3-hydroxy-2-(2,2-dimethylmorpholin-4-yl)-pregnan-11,20-dione (ORG 21465), 2beta-3alpha-5alpha-21-chloro-3-hydroxy-2-(4-morpholinyl)-pregnan-20-one (ORG 20599), and alphaxalone was determined in conjunction with plasma concentrations in rats. For each neuroactive steroid the PK/PD correlation was described on the basis of a two-compartment pharmacokinetic model with an effect compartment to account for hysteresis. The observed concentration EEG effect relationships were biphasic and characterized with a mechanism-based pharmacodynamic model, which is based on a separation between the receptor activation process and the stimulus-response relationship. A single unique biphasic stimulus-response relationship could be identified for all neuroactive steroids, which was successfully described by a parabolic function. The receptor activation process was described by a hyperbolic function. Estimates for the maximum activation (e(PD)) were similar for the different neuroactive steroids but values of the potency estimate (K(PD)) ranged from 157 +/- 16 ng. ml(-1) for pregnanolone, 221 +/- 83 ng. ml(-1) for ORG 20599, and 483 +/- 42 ng. ml(-1) for alphaxalone to 1619 +/- 208 ng. ml(-1) for ORG 21465. A statistically significant correlation was observed between the in vivo potency and the IC(50) in an in vitro [(35)S]t-butylbicyclophosphorothionate binding assay (r = 0.91). It is concluded that the new PK/PD model constitutes a new mechanism-based approach to the quantification of the effects of (synthetic) neuroactive steroids in vivo effects. The results show that the neuroactive steroids differ in potency but not in intrinsic efficacy at the GABA(A) receptor in vivo.