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首页> 外文学位 >Improvement of gastroparesis management by addressing challenges in drug metabolism: Studies with metabolite identification, reaction phenotyping and in vitro drug-drug interactions.
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Improvement of gastroparesis management by addressing challenges in drug metabolism: Studies with metabolite identification, reaction phenotyping and in vitro drug-drug interactions.

机译：通过应对药物代谢方面的挑战来改善胃轻瘫的管理：有关代谢物鉴定，反应表型和体外药物相互作用的研究。

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摘要

Gastroparesis is a disorder characterized by delayed gastric emptying due to chronic abnormal gastric motility. Prokinetic agents such as domperidone and metoclopramide are the cornerstone in treatment of gastroparesis. Although these medications have been used for decades, essential information about their metabolism is not available. Lack of knowledge about the metabolites formed in the body upon administration of the aforementioned medications as well as the enzymes involved in their metabolism limits key information needed to make sound medical decisions. Accurate and comprehensive identification of the metabolites along with reaction phenotyping of prokinetic agents will ensure safe and effective use of these drugs and hence enhance the clinical outcome.;The thesis starts with an introductory chapter which comprises a comprehensive literature review on gastroparesis and the available pharmacological treatment options. The chapter also emphasizes the importance of metabolic profiling of prokinetic agents (domperidone and metoclopramide) and its impact on enhancing the safety and efficacy of these medications.;Chapter 2 of this project was aimed to determine phase oxidative and conjugative metabolites of domperidone in the plasma and urine of gastroparesis patients using tandem mass spectrometry. First, the metabolites were identified in in-vitro human subcellular fractions. The knowledge gained in this experiment helped identifying the metabolites in the biological fluids of patients. In total, 12 metabolites including 7 new metabolites were identified, 5 of which were not reported previously.;Chapter 3 aimed to identify the cytochrome P450 (CYP) enzymes responsible for the metabolism of metoclopramide. The parent depletion approach was used and a novel LC-MS/MS method was developed and validated to enable metoclopramide quantification. CYP2D6 was showed to the predominant isoform in metoclopramide metabolism; other isoforms also contribute to a minor extent.;Chapter 4 discusses the possibility of potential drug-drug interaction (DDI) in the current management practice of gastroparesis. We identified and investigated some frequently used drug combinations that are known to share common metabolic pathways. Domperidone in combination with pioglitazone and ondansetron was evaluated. Results showed that pioglitazone inhibited domperidone metabolism in-vitro. Our experiments did not predict a DDI for the domperidone - ondansetron combination.;In summary, the ultimate goal of this thesis was to improve the management of gastroparesis by increasing information about the metabolic disposition of prokinetic agents and to investigate the magnitude of putative drug combinations. The knowledge provided by this work will help in making more effective and less hazardous clinical decisions which will ultimately lead to more successful gastroparesis management.
机译：胃轻瘫是一种由于慢性胃蠕动异常而导致胃排空延迟的疾病。诸如多潘立酮和胃复安等促动力剂是治疗胃轻瘫的基石。尽管这些药物已经使用了数十年，但仍无法获得有关其代谢的基本信息。缺乏对上述药物给药后体内形成的代谢物及其代谢酶的了解，限制了做出合理医疗决定所需的关键信息。代谢物的准确，全面鉴定以及促运动剂的反应表型将确保这些药物的安全有效使用，从而提高临床疗效。论文从引言一章开始，该章包括有关胃轻瘫的全面文献综述和现有药理学治疗选择。本章还强调了促运动剂（多潘立酮和甲氧氯普胺）的代谢谱分析的重要性及其对增强这些药物安全性和有效性的影响。;该项目的第2章旨在确定血浆中多潘立酮的相氧化和共轭代谢产物串联质谱法测定胃轻瘫患者的尿液和尿液。首先，在体外人类亚细胞级分中鉴定出代谢物。在该实验中获得的知识有助于鉴定患者生物液中的代谢产物。总共鉴定出12种代谢物，包括7种新的代谢物，其中5种以前没有报道过;第3章旨在鉴定负责甲氧氯普胺代谢的细胞色素P450（CYP）酶。使用了母体耗竭方法，并开发并验证了一种新的LC-MS / MS方法以实现胃复安定量。 CYP2D6显示为甲氧氯普胺代谢的主要亚型；其他同工型在较小程度上也有贡献。第4章讨论了当前胃轻瘫的管理实践中潜在的药物-药物相互作用（DDI）的可能性。我们确定并研究了一些已知具有共同代谢途径的常用药物组合。评价了多潘立酮与吡格列酮和恩丹西酮的组合。结果表明吡格列酮体外抑制多潘立酮的代谢。我们的实验没有预测多潘立酮-恩丹西酮组合的DDI。总而言之，本论文的最终目标是通过增加有关促运动剂代谢处置的信息并研究推定药物组合的程度来改善胃轻瘫的管理。 。这项工作提供的知识将有助于做出更有效，更不危险的临床决策，最终将使胃轻瘫的治疗更加成功。

著录项

  • 作者

    Youssef, Amir S.;

  • 作者单位

    Temple University.;

  • 授予单位 Temple University.;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 188 p.
  • 总页数 188
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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