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

机制负责治疗性化合物的血药浓度在急性肾功能衰竭被显著改变。研究表明，一种代表性化合物奎尼丁的蛋白质未结合部分在急性肾功能衰竭中减少，而那些酸性化合物，如甲磺丁酰胺，已知会增加。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α -1酸性糖蛋白（AGP）增加有关，导致血浆AGP浓度升高。此外，我们还发现，当肾功能受损时，脑脊液（CSF）的锂配置减少，而NKCC1的脉络膜丛表达在急性肾功能衰竭时增加。因此，有可能是由于脉络膜丛中NKCC1表达增加，导致脑脊液中锂外排增加，从而减少了对脑脊液的锂配置。我们还发现，通过刺激支配胃肠道的传入神经元上表达的阳离子通道TRPV1，转运体介导的头孢氨苄肠吸收受到抑制。传入神经元似乎在急性肾功能衰竭中调控肠道药物吸收及其交替中起着重要作用，有待进一步研究阐明。

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.