For mechanism-based investigations on PK-PD relationships following intranasal administration, the use of advanced animal models and analytical techniques are crucial. As described in this thesis,... Show moreFor mechanism-based investigations on PK-PD relationships following intranasal administration, the use of advanced animal models and analytical techniques are crucial. As described in this thesis, quantitative information on distinction between extent as well as rate of absorption between nose-to-systemic and nose-to-brain distribution can now be obtained. Using plasma prolactin concentrations as a biomarker for dopamine D2 inhibition, a mechanism-based PK-PD model was developed. Most important aspects in this approach were incorporation of target site exposure (brain extracellular fluid) of remoxipride and a biological system response (positive feedback) mechanism on the synthesis of prolactin, thereby increasing the mechanistic insight in modulation of the dopaminergic system in rats. Simulating remoxipride brain extracellular fluid concentrations in humans, allometric scaling and use of independent information on interspecies differences proved that the structural model is applicable in both rats and man. Show less
