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Study on the Pharmacokinetics Characteristics and Mechanism of Absorption and Transport for GLSBr Series of Compounds

Author: CaiJun
Tutor: XiongYuQing
School: Nanchang University
Course: Pharmacology
Keywords: GLSBr series of compounds Pharmacokinetics Distributed Absorption, transport Caco-2 cells
CLC: R96
Type: Master's thesis
Year: 2008
Downloads: 65
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Abstract

Background and purpose: anti-HBV drugs widely used in clinical multi nucleoside compounds, resistance and withdrawal relapse rate has become more evident. GLSBr Nonnucleoside series is a chemically synthesized compound, which in the animal body the outer test has presented a new mechanism of action and the remarkable effect of the anti-HBV. However, at least 40% of the new compounds is because of the absorption, distribution, metabolism and excretion characteristics not ideal to be eliminated. Therefore, the proven GLSBr series of compounds pharmacokinetic characteristics and absorption mechanism is its ability to be innovative key anti-HBV drugs. Pharmacokinetic characteristics, this paper aims to test the study GLSBr series compounds proved its advantages compound absorption mechanisms, and provide experimental and theoretical basis for the preferred and R \u0026 D for GLSBr series of compounds. Methods: 1. Exploration and the establishment of the RP-HPLC method for detection GLSBr series of compounds of biological samples, and systematic methodological study. To select 48 SD rats were randomly divided into 12 groups, respectively gavage or intravenous injection of high and low two-dose group of the GLSBr-the GLSBr-2 and GLSBr-3 solution, since rats administered before and after the administration of retrobulbar venous plexus series of blood samples by RP-HPLC detect GLSBr blood concentration. Use DAS2.0 the software calculating GLSBr series of compounds of the main pharmacokinetic parameters. Another 24 SD rats were randomly divided into 6 groups, respectively, by intravenous injection of GLSBr-1, GLSBr-2 and GLSBr-3 solution, 10min after administration, 2h were decapitated, blood and liver, kidney, brain tissue. RP-HPLC determination of the tissue concentration of GLSBr series compounds. RP-HPLC Test GLSBr-3 suspicious metabolites selection of the basic structure of the LC-MS-MS qualitative analysis of metabolites, and exploration and create a prototype and metabolites of GLSBr-3 LC-MS detection method, quantitative determination and analysis comparing plasma and tissue GLSBr-3 prototype and the metabolite concentration differences. 4 and a comprehensive evaluation of the characteristics of Caco-2 cell monolayer model, using the Caco-2 cell model test observation preferred GLSBr-3 absorption and transport processes; inspection time, substrate concentration, the temperature of the system, the culture medium pH value and P-gp inhibitors Ver GLSBr-3 uptake in Caco-2 cells; RP-HPLC determination of Caco-2 cells inside and outside GLSBr-3 concentration. And the use of SPSS12.0 analysis and statistical treatment of cells in Excel 2003 software test data obtained to explore GLSBr-3 in Caco-2 cell uptake and absorption of the way. Results: 1. The established plasma samples and tissue samples RP-HPLC/LC-MS detection methods with high sensitivity and specificity, methodological study results in line with the requirements of the analysis of biological samples. 2.GLSBr-1 and GLSBr-2 in vivo process comply with the two-compartment model; When 80mg/kg GLSBr-1, 11mg/kg GLSBr-2, in line with the first-order kinetics, GLSBr-1 and GLSBr-2 in rats the The body of t1/2z were 4.56 ± 1.67h and 0.95 ± 1.21h; stay in the body and GLSBr-1 than GLSBr-2 (P lt; 0.05); GLSBr-3 in the RP-HPLC detection conditions can not be measured. Intravenous injection of different doses of GLSBr-1 and GLSBr-2 in the liver and kidney tissue could measured the concentration of which the highest liver concentration: 1.25 ± 0.23 and 0.61 ± 0.27μg · mL-1; kidney concentration followed by: 0.51 ± 0.37 and 0.26 ± 0.08μg · mL-1; GLSBr-1 in the brain measured concentration of 0.34 ± 0.10μg · mL-1, while GLSBr-2 in the brain tissue can not be measured. This tissue distribution characteristics conducive to play GLSBr-1 and GLSBr-2 in the liver of drug action. 4 in rat plasma, RP-HPLC detection does not appear the peaks of GLSBr-3, another concentration is closely related to the suspected metabolic peak but stable, LC-MS-MS analysis of the test, the metabolite is GLSBr The -3 by C21H22N4O3FSBr molecular ester bond hydrolysis C19H18N4O3FSBr from. LC-MS detection results show that the mouse plasma concentration GLSBr-3 of this metabolism is higher than the concentration of unchanged drug;-3 concentration was significantly higher than the metabolites in liver and kidney tissues GLSBr and GLSBr-3 the highest concentration in the liver: 0.79 ± 0.08μg · mL-1, it lasted for more than 8h, that GLSBr-3 with hepatic tend distribution advantage. 5.Caco-2 cell uptake GLSBr-3 and increased with increasing time in the concentration range of 6.25 ~ 50μg/mL saturation phenomenon, increasing linearly along with the increase in the concentration GLSBr-3 intake, does not appear, but temperature has a significant impact on GLSBr-3 intake (P lt; 0.05), the PDR value of 1.335 ± 0.141, suggesting that Caco-2 cell uptake GLSBr-3 passive diffusion and active transport in two ways. Can not because of the specificity of P-gp inhibitors verapamil affect GLSBr-3 intake, so GLSBr-3 may not be a substrate for P-gp. Conclusion: The established GLSBr series compounds and metabolites RP-HPLC/LC-MS of detection methods can be used for the study of the test; GLSBr-1 and GLSBr-2 in rats in vivo pharmacokinetics of the process in line with the two-compartment model features, GLSBr The distribution characteristics of the series of compounds in rat tissues is liver gt; kidney in gt; brain, which advantageously in its role of anti-HBV in the liver; the Though GLSBr-3 in vivo by hydrolysis of the ester bond quickly generate metabolites C19H18N4O3FSBr, but mice hepatic GLSBr-3 concentration was significantly higher than the metabolites and GLSBr-3 very long residence time in the liver based on effect advantage of GLSBr-3 anti-HBV and liver tends distribution characteristics the likely become GLSBr series most developed The potential compounds; GLSBr-absorption and translocation passive diffusion and active transport participatory.

Study on the Pharmacokinetics Characteristics and Mechanism of Absorption and Transport for GLSBr Series of Compounds

Abstract

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