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Mechanisms responsible for interindividual variability of bioavailability of therapeutic compounds in patients with acute renal failure and related homeostasis perturbation

急性肾衰竭患者治疗化合物生物利用度个体差异及相关稳态扰动的机制

基本信息

批准号：
18590141
负责人：
AIBA Tetsuya
金额：
$ 2.45万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Mechanisms responsible for blood concentration of therapeutic compounds being considerably altered in acute renal failure were investigated. It was shown that protein unbound fraction of a representative compound quinidine is decreased in acute renal failure, whereas those of acid compounds, such as tolbutamide, has been known to be increased. The decreased unbound fraction of quinidine seems to be related to the fact that the hepatic production of alpha-1 acid glycoprotein (AGP) increases in acute renal failure, resulting in an increase in the plasma AGP concentration. In addition, we revealed that lithium disposition to cerebrospinal fluid (CSF) decreases when the kidney function is impaired, and that the choroid plexial expression of NKCC1 increases in acute renal failure. Therefore, it is plausible that the decreased lithium disposition to CSF is caused by an increased lithium efflux from CSF due to an increased NKCC1 expression in the choroid plexus. We also found that the transporter-mediated intestinal absorption of cephalexin is suppressed by stimulating a cation channel TRPV1 expressed on afferent neurons innervating gastro-intestinal tract. As afferent neurons seem to play an important role in regulating intestinal drug absorption and its alternation in acute renal failure, future study should be conducted to clarify this.

研究了急性肾衰竭时治疗化合物的血液浓度发生显着改变的机制。结果表明，代表性化合物奎尼丁的蛋白质未结合部分在急性肾衰竭中减少，而酸性化合物（例如甲苯磺丁脲）的蛋白质未结合部分则增加。奎尼丁未结合部分的减少似乎与急性肾功能衰竭时肝脏产生的α-1酸性糖蛋白（AGP）增加，导致血浆AGP浓度增加有关。此外，我们发现，当肾功能受损时，锂在脑脊液（CSF）中的分布会减少，并且在急性肾功能衰竭时，NKCC1的脉络丛表达会增加。因此，脑脊液锂分布减少可能是由于脉络丛中 NKCC1 表达增加导致锂从脑脊液流出增加所致。我们还发现，通过刺激在支配胃肠道的传入神经元上表达的阳离子通道TRPV1，可以抑制转运蛋白介导的头孢氨苄肠道吸收。由于传入神经元似乎在调节肠道药物吸收及其在急性肾功能衰竭中的变化中发挥着重要作用，因此未来的研究应该阐明这一点。