Mechanism-based pharmacokinetic/pharmacodynamic modeling of the electroencephalogram effects of GABAA receptor modulators: in vitro-in vivo correlations.

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 GABAA receptor modulators. The EEG effects of nine prototypical GABAA receptor modulators (six benzodiazepines, one imidazopyridine, one cyclopyrrolone, and one beta-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 (EC50) and intrinsic activity between the compounds.

Pharmacokinetic-pharmacodynamic analysis of the EEG effect of alfentanil in rats following beta-funaltrexamine-induced mu-opioid receptor "knockdown" in vivo.

Purpose: The objective of this investigation was to determine the influence of pre-treatment with the irreversible mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA) on the pharmacokinetic-pharmacodynamic (PK/PD) relationship of alfentanil in rats.

Methods: The PK/PD correlation of alfentanil (2 mg x kg(-1) intravenously in 20 min) was determined in chronically instrumented rats using amplitudes in the 0.5-4.

Influence of different fat emulsion-based intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol.

Purpose: The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint.

Methods: Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats.

Pharmacokinetic-pharmacodynamic modelling of the EEG effect of alfentanil in rats.

The purpose of the present investigation was to develop a methodology for quantification of the concentration-pharmacological effect relationship of alfentanil in individual rats by using effect parameters derived from quantitative EEG analysis. In particular, the role of the opioid-induced side effects of proconvulsant activity, hypothermia, and respiratory depression was investigated. Amplitudes in the 0.

Modeling of the effect site equilibration kinetics and pharmacodynamics of racemic baclofen and its enantiomers using quantitative EEG effect measures.

The plasma to effect site equilibration kinetics and the steady-state plasma concentration-EEG effect relationship of baclofen were characterized after separate administration of racemic baclofen and its two enantiomers. Male Wistar-derived rats received an i.v.