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首页> 外文学位 >Effects of chronic kidney disease on drug disposition: Transport, metabolism, and pharmacokinetics of different biopharmaceutics drug disposition classification system (BDDCS) drugs.
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Effects of chronic kidney disease on drug disposition: Transport, metabolism, and pharmacokinetics of different biopharmaceutics drug disposition classification system (BDDCS) drugs.

机译：慢性肾脏疾病对药物处置的影响：不同生物药物药物处置分类系统（BDDCS）药物的转运，代谢和药代动力学。

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摘要

Pharmacokinetic changes of non-renally excreted drugs have been observed in chronic kidney disease (CKD) patients. Typically, dose adjustment is implemented in CKD patients for drugs that are renally excreted, but not for non-renally excreted drugs. I hypothesized that uremic toxins in CKD patients alter the transport of drugs and consequently alter drug disposition. Since BDDCS categorize drugs based on drug transporter involvement for drug disposition, I also hypothesized that BDDCS can be used as a tool to predict which drugs (Class 2, 3, and 4 but not Class 1) would have changes in drug disposition in CKD patients.;Uremic toxins in CKD may alter drug metabolism; however, uremic toxins have not been investigated for their effect on drug transporters. In this thesis I investigated if uremic toxins affect drug transport in tranfected cells (transfected with human hepatic transporters), and rat and human hepatocytes. I observed no change in drug transport for the Class 1 drug propranolol, but reduction in transport for Class 2 losartan and Class 4 eprosartan in transfected cells. On the other hand, in rat and human hepatocytes, changes were only observed for losartan. There was no change in metabolism in rat or human microsomes for propranolol or losartan in the presence of hemodialysis (HD) serum.;Studies have shown that hepatic transporters play an important role in drug disposition, but changes in hepatic drug transporters in CKD have not been explored. I used a rat model chronic kidney disease and investigated the hepatic drug disposition of propranolol, losartan, and eprosartan in the isolated perfused rat liver system by perfusing the liver with HD serum or normal serum. The results from these studies were inconclusive, the variability was high and the number of animals used was small.;A human clinical study was carried out in CKD patients and healthy volunteers. I investigated the pharmacokinetic changes of propranolol, losartan, and erythromycin. As predicted there were no changes in propranolol PK, but there were significant changes for losartan metabolite and erythromycin. This showed that BDDCS can be a useful tool for predicting changes in drug disposition in CKD patients.
机译：在慢性肾脏疾病（CKD）患者中已观察到非肾脏排泄药物的药代动力学变化。通常，对肾脏排泄的药物在CKD患者中进行剂量调整，但对于非肾脏排泄的药物则不进行剂量调整。我假设CKD患者的尿毒症毒素会改变药物的运输，从而改变药物的处置方式。由于BDDCS是根据药物转运体对药物处置的影响对药物进行分类的，因此我还假设BDDCS可以用作预测CKD患者中哪些药物（第2、3和4类，而不是第1类）会改变药物处置的工具。; CKD中的尿毒症毒素可能会改变药物代谢；然而，尚未研究尿毒症毒素对药物转运蛋白的作用。在本论文中，我研究了尿毒症毒素是否影响转染细胞（用人肝转运蛋白转染）以及大鼠和人肝细胞中的药物转运。我观察到，第1类药物普萘洛尔的药物转运没有改变，但在转染的细胞中第2类氯沙坦和第4类依普罗沙坦的转运减少了。另一方面，在大鼠和人的肝细胞中，仅观察到氯沙坦的变化。在存在血液透析（HD）血清的情况下，对大鼠或人的微粒体中普萘洛尔或氯沙坦的代谢没有改变。被探索了。我使用了大鼠慢性肾脏疾病模型，并通过向肝脏灌注HD血清或正常血清，研究了分离的灌注大鼠肝脏系统中普萘洛尔，氯沙坦和依普罗沙坦的肝药物处置。这些研究的结果尚无定论，变异性高，使用的动物数量少。；在CKD患者和健康志愿者中进行了人体临床研究。我调查了普萘洛尔，氯沙坦和红霉素的药代动力学变化。如预测的那样，普萘洛尔PK没有变化，但是氯沙坦代谢物和红霉素有显着变化。这表明BDDCS可以作为预测CKD患者药物处置变化的有用工具。

著录项

  • 作者

    Reyes, Maribel.;

  • 作者单位

    University of California, San Francisco.;

  • 授予单位 University of California, San Francisco.;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 172 p.
  • 总页数 172
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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