The Pharmacokinetics And Tissue Distribution Study Of Tetradecyl2,3-dihydroxybenzoate

Alzheimer’s disease (AD) is a chronic disease commonly seen among elderly people, and there is no drug available to fundamentally cure it. On the basis of structure activity relationship study of novel alkyl benzoates from Gentiana rigescens (Franch.), our group had determined tetradecyl2,3-dihydroxybenzoate (ABG-001) to be the lead compound against AD. Its in vivo/in vitro activity, mechanism of action and safety evaluation had also been studied. In order to further supplement the druggability evaluation of ABG-001, the pharmacokinetics study and tissue distribution study of ABG-001has been done on rats in this thesis.In this thesis, a HPLC method has been developed and validated to analyze the ABG-001concentration in rat’s blood plasma. The method had a linear range from0.1μg/mL to50μg/mL to give a calibration curve of y=1.7141x+0.05(r2=0.9992); The intra-and inter-day RSD was less than8%. The accuracy was between93.1-107.2%. This method was applied to the pharmacokinetics study of ABG-001. The result showed that after the oral administration of ABG-001at the dose of100mg/kg, the Tmax was5h, the Cmax was0.81μg/mL, the t1/2was3.4h. After the intravenous injection of ABG-001at the dose of10mg/kg, the t1/2was14.07min, suggesting that the speed of distribution and elimination were very quick. The absolute bioavailability of ABG-001was8.88%.Also, a HPLC method has been developed to analyze the ABG-001concentration in rat’s tissues. And this method has been validated on the tissues of heart, lung, stomach, intestine, spleen, and applied to the ABG-001tissue distribution after oral administration of100mg/kg. In the time points of2h (absorption phase),5h (peak point),7h (elimination phase), the rats were executed and the brain, heart, liver, spleen, stomach, lung, kidney, intestine, testes, muscle, fat and stomach contents were taken out for ABG-001analysis. The result showed that, the ranking of tissue exposure to ABG-001was stomach content, intestine, stomach, heart, spleen, lung, liver and others from high to low. This result showed the ABG-001was mainly distributed in digestive tract. In most tissues, the ABG-001concentration was relatively high at2h, and reaching its peak at5h point; at the7h point, the concentration was largely reduced, showing the elimination speed was relatively high after5h point.