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

对急性肾功能衰竭时治疗药物血药浓度显著改变的机制进行了研究。研究表明，在急性肾功能衰竭时，具有代表性的化合物奎尼丁的蛋白质游离部分减少，而酸性化合物，如甲苯磺丁胺的蛋白质游离部分已知增加。奎尼丁游离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，从而导致血浆AGP浓度升高有关。此外，我们还发现，当肾功能受损时，锂对脑脊液(CSF)的处置减少，而在急性肾功能衰竭时，NKCC1的脉络丛表达增加。因此，可能是由于脉络丛中NKCC1表达增加，导致脑脊液锂离子外流增加所致。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，头孢氨苄的转运体介导的肠道吸收受到抑制。由于传入神经元似乎在调节急性肾功能衰竭时肠道药物吸收及其变化中发挥着重要作用，因此未来的研究应该澄清这一点。

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.