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Investigation of rapamycin and rapamycin metabolites.

机译：雷帕霉素和雷帕霉素代谢产物的研究。

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摘要

Rapamycin is an immunosuppressive drug used in organ transplantation. It is metabolised to a number of products. It is not known what the relevance of these metabolites is---if they posses immunosuppressive, or toxic activity; what their concentrations are in blood; if they should be monitored clinically in transplant patients. To answer these questions, rapamycin metabolites were tested extensively. First, metabolites were generated using a microbial system expressing cytochrome P450 3A enzyme. The metabolites were purified and five metabolites were structurally identified by high performance liquid chromatography with mass spectrometry detection (HPLC-MS). They have been named according to the structural change(s) they posses: 27-, 39-O-di-demethylrapamycin, C(1--14)-hydroxyrapamycin, C(15--27)hydroxyrapamycin, 16-O-demethylrapamycin and 39-O-demethylrapamycin. The immunosuppressive activity of these metabolites was evaluated using the mixed lymphocyte reaction. The immunosuppressive activity of the metabolites ranged from 0.1% to 17.3% of rapamycin. The toxic activity of these metabolites was investigated in an in vitro vascular endothelial vasoactive substance release assay; results confirm that it is not an important mode of toxicity for rapamycin or its metabolites. A method was developed for measurement of five metabolites in clinical and research specimens by HPLC-MS. A study investigating differences in canine portal and systemic pharmacokinetics of rapamycin revealed rapamycin oral dosing produces an appropriate pharmacokinetic profile for liver and portal vein embolised pancreatic islet transplantation, as differences between portal and systemic peak levels were negligible. Rapamycin and rapamycin metabolite levels were also measured in liver transplant patients on a compassionate release program. None of the five metabolites evaluated were present in concentrations that exceeded 30% of rapamycin in these liver transplant patients. Overall, given the new information on the concentrations and immunosuppressive activities, the five metabolites tested do not contribute significantly to immunosuppression. While further study of the metabolites of rapamycin should be pursued, at this time rapamycin alone should be measured for therapeutic drug monitoring and dosage adjustment in transplant patients.
机译：雷帕霉素是一种用于器官移植的免疫抑制药物。它被代谢为多种产品。这些代谢物的相关性是未知的，如果它们具有免疫抑制或毒性作用；它们在血液中的浓度是多少；是否应在移植患者中进行临床监测。为了回答这些问题，对雷帕霉素代谢产物进行了广泛的测试。首先，使用表达细胞色素P450 3A酶的微生物系统生成代谢物。通过高效液相色谱-质谱检测（HPLC-MS）纯化代谢物并在结构上鉴定出五种代谢物。根据其所发生的结构变化对它们进行了命名：27-，39-O-二-去甲基雷帕霉素，C（1--14）-羟基雷帕霉素，C（15--27）羟基雷帕霉素，16-O-去甲基雷帕霉素和39-O-去甲基雷帕霉素。使用混合淋巴细胞反应评估了这些代谢产物的免疫抑制活性。代谢产物的免疫抑制活性为雷帕霉素的0.1％至17.3％。在体外血管内皮血管活性物质释放试验中研究了这些代谢产物的毒性。结果证实这不是雷帕霉素或其代谢产物的重要毒性模式。开发了一种通过HPLC-MS测定临床和研究样本中五种代谢物的方法。一项研究雷帕霉素犬门静脉和全身药代动力学差异的研究表明，雷帕霉素口服给药可为肝脏和门静脉栓塞胰腺胰岛移植提供适当的药代动力学特征，因为门静脉和全身峰值水平之间的差异可忽略不计。还按照同情释放程序对肝移植患者的雷帕霉素和雷帕霉素代谢物水平进行了测定。在这些肝移植患者中，所评估的五种代谢物均不超过雷帕霉素浓度超过30％。总体而言，鉴于有关浓度和免疫抑制活性的新信息，所测试的五种代谢产物对免疫抑制的贡献不大。虽然应进一步研究雷帕霉素的代谢产物，但此时应单独测量雷帕霉素以监测移植患者的治疗药物并调整剂量。

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  • 作者

    Gallant-Haidner, Heather Lee.;

  • 作者单位

    University of Alberta (Canada).;

  • 授予单位 University of Alberta (Canada).;
  • 学科 Health Sciences Pathology.; Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 199 p.
  • 总页数 199
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 病理学;药理学;
  • 关键词

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