Mechanisms of The Increased Bioavailability of Drugs During Renal Failure

据报道，心得安在肾功能衰竭患者体内的生物利用度增加，未进行血液透析的肾功能衰竭患者口服心得安的血药浓度-时间曲线下面积是健康志愿者的7-8倍。为了探讨普萘洛尔在肾功能不全时生物利用度提高的机制，我们利用几种实验性大鼠肾损伤模型研究了普萘洛尔的药物代谢和药代动力学。我们报道，普萘洛尔在顺铂肾功能不全大鼠体内生物利用度的提高主要是由于肝脏首过代谢的部分饱和导致肠道吸收增加所致。然而，在双侧输尿管结扎(BUL)诱导的肾功能衰竭中，普萘洛尔和美托洛尔因饱和动力学导致的肝脏首过清除量的吸收速率依赖性下降是微乎其微的，而BUL大鼠肝脏代谢活性和药物提取显著减少可能是由于肝脏中NADPH生成率的降低。另一方面，在手术和药物诱导的肾功能障碍大鼠中，评估了P450的肝脏和肠道代谢活性。然后我们发现：(A)在肾功能衰竭时，只有选定的肝脏P450代谢活性降低，(B)肝脏P450代谢活性降低的程度取决于肾功能衰竭的病因，以及(C)肠中CYP3A代谢活性的改变并不总是与肝脏中的相关。此外，为了进一步表征药物在肠道的吸收，我们建立了一种利用Caco-2细胞单层来评估药物跨细胞转运的测试系统。这些发现可能为研究药物在肾功能衰竭时的生物利用度变化提供新的视角。

It has been reported that the bioavailability of propranolol was increased in patients with renal failure, and that the area under the concentration-time curve for orally administered propranolol in renal failure patients not on hemodialysis is 7-to 8-fold higher than that in healthy volunteers. To investigate the mechanisms responsible for the increased bioavailability of propranolol in renal dysfunction, we studied the drug metabolism and pharmacokinetics using several experimental rat models with renal impairment.We reported that the increased bioavailability of propranolol in rats with cisplatin-induced renal dysfunction was mainly a result of the increased absorption rate in the intestine followed by the partial saturation of hepatic first-pass metabolism. However, in bilateral ureter ligation (BUL)-induced renal failure, the absorption rate-dependent decrease in hepatic first-pass clearance of propranolol and metoprolol due to saturation kinetics is marginal, and the hepatic metabolic activity and extraction of the drugs is significantly decreased in BUL rats probably due to the reduced NADPH generation rate in the liver.On the other hand, the hepatic and intestinal metabolic activities of P450 were evaluated in rats with surgery-and drug-induced renal dysfunction. Then we found (a) that only selected P450 metabolic activity in the liver is decreased in renal failure, (b) that extent of the decrease in hepatic metabolic activities of P450 is dependent on the etiology of renal failure, and (c) that alteration of CYP3A metabolic activity in the intestine is not always correlated with that in the liver. In addition, to further characterize the intestinal absorption of drugs, we established an assay system evaluating transcellular drug transport using Caco-2 cell monolayers.These findings may provide new insight into the altered bioavailability of drugs during renal failure.