ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS-MECHANISMS

改变阴离子药物的肝脏处置机制

基本信息

  • 批准号:
    7433463
  • 负责人:
  • 金额:
    $ 4.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1991
  • 资助国家:
    美国
  • 起止时间:
    1991-04-01 至 2009-06-30
  • 项目状态:
    已结题

项目摘要

Altered hepatic disposition of anionic drugs secondary to drug interactions, chemical exposure, disease states or genetic predisposition has important therapeutic implications. Systemic exposure, and therefore the magnitude and duration of pharmacologic response, may be affected substantially by changes in hepatic translocation of drugs. Likewise, perturbations in hepatic transport can influence systemic, intestinaland, perhaps most importantly, hepatic toxicity. The long-term objective of this ongoing research program is to develop a mechanistic understanding of how alterations in hepatic transport influence overall hepatobiliary disposition of anionic drugs and derived metabolites. A multiexperimental approach incorporating relevant in vitro expression systems (Sf9 cells, Xenopus laevis oocytes); a novel sandwich-cultured (SC) primary hepatocyte model that retains hepatic transport mechanisms, provides quantitative data on biliary and basolateral excretion, and is amenable to transporter knockdown by RNAi; isolated perfused livers usingTR" rats, a model of Mrp2 deficiency; and an in vivo human study will be employed to elucidate mechanisms and consequences of altered hepatic transport of model anionic substrates. The hypothesis that multiple Mrp isoforms contribute to basolateral excretion of anionic drugs and metabolites from the liver will be tested, proteins that contribute significantly to this process will be identified, and kinetics of transport will be determined for model substrates. Purportedly "specific" inhibitors of hepatic canalicular transport may interact with basolateral transport proteins, resulting in a previously unrecognized category of drug-drug interactions. The ability of these inhibitors to modulate basolateral excretion, and the consequences of such modulation on hepatobiliary disposition, will be explored. The hypothesis that hepatic response mechanisms (basolateral exporters, other canalicular transporters, and hepatic Phase II enzymes) compensate for impaired Mrp2 function will be evaluated; the role of nuclear hormone receptors in these compensatory responses, and the kinetic consequences of such compensation, will be defined. Finally, the ability of human SC hepatocytes to predict hepatobiliary disposition of a model anion in humans will be assessed with a novel clinical protocol that allows quantitation of biliary excretion in healthy humans. Elucidating mechanisms of hepatic transport, and identifying functional consequences of alterations in these processes, is an important step in understanding the multiplicity of factors that determine systemic exposure (and ultimately biologic response) to xenobiotics, and is prerequisite to exploiting these processes to achieve desirable therapeutic outcomes.
阴离子药物继发于药物相互作用、化学暴露、疾病状态的肝脏处置改变

项目成果

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KIM L.R. BROUWER其他文献

KIM L.R. BROUWER的其他文献

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{{ truncateString('KIM L.R. BROUWER', 18)}}的其他基金

Duke-UNC Collaborative Pediatric Clinical Pharmacology Postdoctoral Training Program
杜克大学-北卡罗来纳大学合作儿科临床药理学博士后培训项目
  • 批准号:
    10400677
  • 财政年份:
    2021
  • 资助金额:
    $ 4.45万
  • 项目类别:
Duke-UNC Collaborative Pediatric Clinical Pharmacology Postdoctoral Training Program
杜克大学-北卡罗来纳大学合作儿科临床药理学博士后培训项目
  • 批准号:
    10626740
  • 财政年份:
    2021
  • 资助金额:
    $ 4.45万
  • 项目类别:
Duke-UNC Collaborative Pediatric Clinical Pharmacology Postdoctoral Training Program
杜克大学-北卡罗来纳大学合作儿科临床药理学博士后培训项目
  • 批准号:
    10173438
  • 财政年份:
    2021
  • 资助金额:
    $ 4.45万
  • 项目类别:
Mechanisms of Altered Hepatic Transport: Impact on Drug Therapy
肝脏转运改变的机制:对药物治疗的影响
  • 批准号:
    10406459
  • 财政年份:
    2017
  • 资助金额:
    $ 4.45万
  • 项目类别:
Mechanisms of Altered Hepatic Transport: Impact on Drug Therapy
肝脏转运改变的机制:对药物治疗的影响
  • 批准号:
    9906256
  • 财政年份:
    2017
  • 资助金额:
    $ 4.45万
  • 项目类别:
Mechanisms of Altered Hepatic Transport: Impact on Drug Therapy
肝脏转运改变的机制:对药物治疗的影响
  • 批准号:
    10598589
  • 财政年份:
    2017
  • 资助金额:
    $ 4.45万
  • 项目类别:
Mechanisms of Altered Hepatic Transport: Impact on Drug Therapy
肝脏转运改变的机制:对药物治疗的影响
  • 批准号:
    9277071
  • 财政年份:
    2017
  • 资助金额:
    $ 4.45万
  • 项目类别:
UNC-Duke Collaborative Clinical Pharmacology Postdoctoral Training Program
北卡罗来纳大学-杜克大学合作临床药理学博士后培训项目
  • 批准号:
    10434641
  • 财政年份:
    2011
  • 资助金额:
    $ 4.45万
  • 项目类别:
UNC-Duke Collaborative Clinical Pharmacology Postdoctoral Training Program
北卡罗来纳大学-杜克大学合作临床药理学博士后培训项目
  • 批准号:
    10645033
  • 财政年份:
    2011
  • 资助金额:
    $ 4.45万
  • 项目类别:
UNC-Duke Collaborative Clinical Pharmacology Postdoctoral Training Program
北卡罗来纳大学-杜克大学合作临床药理学博士后培训项目
  • 批准号:
    10090199
  • 财政年份:
    2011
  • 资助金额:
    $ 4.45万
  • 项目类别:

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临床记录中缩写词的实时消歧
  • 批准号:
    8077875
  • 财政年份:
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  • 资助金额:
    $ 4.45万
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Real-time Disambiguation of Abbreviations in Clinical Notes
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  • 批准号:
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  • 资助金额:
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  • 项目类别:
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临床记录中缩写词的实时消歧
  • 批准号:
    8305149
  • 财政年份:
    2010
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