Mechanisms of The Increased Bioavailability of Drugs During Renal Failure

据报道，普萘洛尔的生物利用度在肾衰竭患者中增加，并且在未进行血液透析的肾衰竭患者中口服普萘洛尔的浓度-时间曲线下面积比健康志愿者高7- 8倍。为探讨普萘洛尔在肾功能不全时生物利用度增加的机制，我们采用几种实验性肾功能不全大鼠模型研究了普萘洛尔的药物代谢和药代动力学，结果表明，普萘洛尔在顺铂所致肾功能不全大鼠中的生物利用度增加主要是由于肠吸收速率增加和肝脏首过代谢部分饱和所致。然而，在双侧输尿管结扎（BUL）诱导的肾衰竭中，由于饱和动力学，普萘洛尔和美托洛尔的肝脏首过清除率的吸收率依赖性降低是边缘的，并且BUL大鼠中药物的肝脏代谢活性和提取显著降低，可能是由于肝脏中NADPH生成速率降低。在手术和药物诱导的肾功能不全大鼠中评价了P450的肝和肠代谢活性。我们发现：（a）在肾衰竭时，只有肝脏中选定的P450代谢活性降低;（B）P450肝脏代谢活性降低的程度取决于肾衰竭的病因;（c）肠中CYP 3A代谢活性的改变并不总是与肝脏中的代谢活性相关。此外，为了进一步表征药物在肠道的吸收，我们建立了一个利用Caco-2细胞单层评价药物跨细胞转运的测定系统，这些发现可能为肾衰竭期间药物生物利用度的改变提供新的见解。

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.