ZhUK M. The pharmacogenetical peculiarity of biokinetics of the of ligands of the GABAA receptor

The dissertation is devoted to the experimental study and mathematical modelling of interactions in vivo between exogenous ligands of the GABA receptor complex. Functional properties of the GABA receptor complex were examined in vivo on the basis of interactions between lidands of different subunits of the GABA receptor (muscimol, flumazenil and ethanol) and in conditions of altered levels of the endogenous mediator. Mechanism of in vivo action of phenazepam, muscimol, Ro 15-1788 and ethanol were described using pharmacological models. The relationship between pharmacokinetics and pharmacodynamics of phenazepam, a novel prodrug - cinazepam and its metabolite - 3-hydroxyphenazepam has been studied in different strains of mice (CBA, C57Bl/6 and their F1). It has been demonstrated that the ethanol pharmacokinetics irrespective of the strains of animals and modifying factors. Analytical formalism is worked out to determine the relationship between drug pharmacokinetics and therapeutic index. The applicability of the mathematical model has been demonstrated during estimation of the ethanol and muscimol biokinetics.