|Hyphenated microdialysis and chromatography to monitoring protein free drug for pharmacokinetic study in rat
|Hyphenated Techniques for Comprehensive Analysis
|Prof Tung-Hu Tsai
|National United University / National Yang-Ming University
|Taiwan, Republic of China
Abstract Information :
To explore the pharmacokinetic of protein unbound drug, a hyphenated microdialysis and chromatography was developed to monitoring the level of protein free drug for absorption, distribution, metabolism and excretion study in rat. The microdialysis membrane is semi-permeable depending on the molecular weight cut-off and does not allow larger molecules penetration. Only protein free drug is permitted to penetrate through microdialysis membrane. Due to the protein free fraction is the pharmacological active form, which is available for pharmacokinetic and pharmacodynamic action. Besides, only protein free form of the drug molecule can be delivered to the target sites for therapeutic actions. Then, this technique is gaining the popularity in preclinical pharmacokinetic and pharmacodynamic studies. To investigate the brain, muscle, liver or kidney distribution of the drugs, single or multiple microdialysis probes has been applied in the experimental animal for blood, brain, muscle, liver, kidney ...etc. multiple targets. The regional brain distribution, the portion of drug that passes through the blood-brain barrier, liver and kidney distribution can be defined by the area under the curve ratio of blood-to-brain, blood-to-liver and blood-to-kidney, respectively. P-glycoprotein (P-gp) is a product of the multidrug resistance gene, which also corresponds to diminished intracellular accumulation of the drugs. P-gp also contributes to the barrier functions of the brain by extruding compounds that are potentially toxic to the brain from the capillary endothelia cells. In addition, biliary excretion has been recognized not only to depend on bile salts secretion, but also to require the active participation of the P-gp. To investigate the mechanism of P-gp modulation on the blood brain barrier and biliary excretion, a P-gp inhibitor was administered in the experimental animal. Furthermore, the pros and cons of microdialysis will be discussed, including the detailed surgical techniques in animal experiments from rat blood, liver and kidney for the analysis of protein-unbound drug.