The role of ENT1 in pharmacokinetics of nucleoside analogues for the treatment of Huntington's disease.
| Autor: | Hui-Ting Yang, 楊惠婷 |
|---|---|
| Rok vydání: | 2015 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 104 Huntington’s disease (HD) is a progressive neurodegenerative disease characterized by chorea and the decline in psychiatric and cognitive functions. The objective of the present study was to investigate the role of ENT1 on the pharmacokinetics of adenosine analogues (compound-B and compound-A). mRNA levels of mouse ENT1 (mEnt1) were analyzed in R6/2 HD transgenic mice and the wild-type (WT) controls. Also, pharmacokinetic properties, including blood to plasma ratios (KB/P), blood concentration versus time curves, brain to blood ratios, and ability of compounds to pass through the blood brain barrier (BBB), of these compounds were evaluated in mENT1 knock out (KO) mice and the wild-type (WT) controls. The results showed that the expression levels of mEnt1 were comparable between R6/2 WT and HD mice. The KB/P of compound-A is approximate to 1 and compound-B is greater than 1, suggesting that compound-B is distributed into red blood cells. For compound-B, the AUC values were 25738±5946、47230±15223 ng×min/mL in mENT1 WT and KO mice, respectively. For compound-A, the AUC values were 19989±1904、28207±4252 ng×min/mL in mENT1 WT and KO mice, respectively. From the data of brain and blood extraction, the brain to blood ratios of compound-A was no difference in WT and KO mince, compound-B was higher in WT mice than in KO mice, whereas this ratio was higher for compound-B than for compound-A. On the other hand, the results of in-vivo brain microdialysis study showed that the brain extracellular levels of compound-A and adenosine tended to increase after an intraperitoneal injection of 10 mg/kg of compound-A, whereas the concentration of compound-B and adenosine remained unchanged after the administration (i.p. 10 mg/kg of compound-B). These data suggest that the expression of mENT1 may have more profound effects on the pharmacokinetics of compound-B than on that of compound-A. However, since it is compound-A but not compound-B that increased brain extracellular levels of adenosine, further study is required to eludicate the pharmacodynamic impact of these findings. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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