| Popis: |
Pharmacokinetic (PK) characterization and in vivo pharmacological properties of new chemical entities are important components during lead compound selection and optimization in the drug discovery process. Accordingly, reliable techniques are needed that can generate the requisite pharmacokinetic/pharmacodynamic (PK/PD) information for an increased number of compounds. When dealing with compounds targeting the central nervous system (CNS), biophase PK may differ significantly from plasma PK, because blood-brain barrier (BBB) transport and brain distribution often do not occur instantaneously and to a full extent. Therefore the brain distributional behaviors are important determinants of in vivo drug effects. In vivo microdialysis technique has been used increasingly over the past years for in vivo sampling of extracellular exogenous compounds in brains of freely moving rats (1-3). The extracellular brain concentration of free drug which measured by microdialysis may reflect the amount of drug available at the pharmacological target. As the microdialysis technique also allows the simultaneous determination of different endogenous substances, such as neurotransmitters, which sometimes represent the efficacy biomarker of a CNS drug, in the same local interstitial environment. Microdialysis is an attractive tool for PK/PD investigations of CNS active drugs (4). However, the extracellular concentration of neurotransmitters in the synaptic cleft is very low which can be in the range of fg/μl; the sampling recovery of microdialysis probe is less than 20%. The application of this technique was highly limited by lack the proper sensitive analytical methods to determine the endogenous substance and exogenous drug. For analysis of endogenous neurotransmitters, such as, serotonin (5-HT), dopamine (DA), noradrenaline (NE), acetylcholine (ACh), histamine, -aminobutyric acid (GABA) and glutamate (Glu), microdialysis in combination with high performance liquid chromatography (HPLC) electrochemical detection (ED) or fluorescence detection has been |
