Transporter-Enzyme Interplay Evaluation via Microfluidiic HTS Cell Culture Device
通过微流控 HTS 细胞培养装置评估转运蛋白-酶相互作用
基本信息
- 批准号:7244054
- 负责人:
- 金额:$ 36.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-06-02 至 2009-05-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAnimal ModelAnimalsApicalBeliefBiological AvailabilityBloodClassCultured CellsDataDevelopmentDevicesDoseDrug KineticsEnterocytesEnzymesEquilibriumEvaluationFailureHepaticHepatocyteHumanIndustryIntestinal AbsorptionIntestinesIntravenousLiverMarketingMeasuresMetabolismMicrofluidicsMicrosomesModelingMolecularPerfusionPharmaceutical PreparationsPharmacologic SubstancePreclinical Drug DevelopmentPublishingRateRattusReportingResearch PersonnelScienceScientistSystemTest ResultTestingTherapeuticTodayToxicologyWorkbiochipconceptdrug developmentdrug metabolismhuman studyin vivomannovelpre-clinicalpredictive modelingprogramstheoriestooluptake
项目摘要
DESCRIPTION (provided by applicant):
Because of numerous past failures, it is the belief of many pharmaceutical scientists that animal models are not useful in predicting human DMPK (drug metabolism and pharmacokinetics) and toxicology. This has promoted initiatives to advance NMEs (new molecular entities) into man as soon as possible with a deemphasis of animal work. Although there can be marked advantages to evaluation of NMEs in humans early in drug development, we do not believe that this is the most efficient or most effective way to select the DMPK-optimal molecule from many potential candidate compounds. We hypothesize that the poor predictability of animal models for highly metabolized compounds (approximately 70% of drugs on the market) is due to our nascent understanding of how to incorporate transporters, both absorptive and efflux, into predictive models of drug metabolism, and this lack of understanding of transporter-enzyme interplay renders traditional drug disposition theory simplistic and inadequate, which accounts for the poor predictability. However, most importantly we lack a simple high-throughput preclinical tool to characterize transporter enzyme interplay that conveniently allows human-animal comparisons. In this application, we describe a novel preclinical tool, the microfluidic cell culture biochip in development by the Hurel Corporation and propose studies to test the applicability of this system to address the issues of concern as outlined in 10 specific aims. We will characterize hepatic and enterocyte transporter-enzyme interplay in the Hurel system, initially separately and then combined, utilizing cultured rat and human hepatocytes and enterocytes for Class 1 and Class 2 highly metabolized compounds. These data will be compared with rat liver and intestinal perfusion, rat and human hepatocyte/enterocyte and microsome studies and whole animal iv dosing pharmacokinetics studies carried out predominantly external to this application. A major focus of the work will be to test the concordance of the Hurel device results with the more laborious animal and human studies and to develop models that will allow prediction of animal preclinical DMPK using the Hurel microfluidic cell culture biochips, as well as address the deficiency of our present models of drug elimination that do not adequately consider transporter-enzyme interplay in drug disposition.
描述(由申请人提供):
项目成果
期刊论文数量(0)
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{{ truncateString('LESLIE Z BENET', 18)}}的其他基金
A Transporter-Based Predictive ADME Platform
基于转运蛋白的预测 ADME 平台
- 批准号:
7804736 - 财政年份:2010
- 资助金额:
$ 36.06万 - 项目类别:
Transporter-Enzyme Interplay Evaluation via Microfluidiic HTS Cell Culture Device
通过微流控 HTS 细胞培养装置评估转运蛋白-酶相互作用
- 批准号:
7429824 - 财政年份:2006
- 资助金额:
$ 36.06万 - 项目类别:
Transporter-Enzyme Interplay Evaluation via Microfluidiic HTS Cell Culture Device
通过微流控 HTS 细胞培养装置评估转运蛋白-酶相互作用
- 批准号:
7012396 - 财政年份:2006
- 资助金额:
$ 36.06万 - 项目类别:
Cyclosporine in Diabetic Renal Transplantation
环孢素在糖尿病肾移植中的应用
- 批准号:
6972242 - 财政年份:2004
- 资助金额:
$ 36.06万 - 项目类别:
P-Gp Expression and Function in Treatment of HIV+ Women
P-Gp 在 HIV 女性治疗中的表达和功能
- 批准号:
6972257 - 财政年份:2004
- 资助金额:
$ 36.06万 - 项目类别:
P-GLYCOPROTEIN EXPRESSION AND FUNCTION IN HIV+ WOMEN
HIV 女性中 P-糖蛋白的表达和功能
- 批准号:
6579420 - 财政年份:2002
- 资助金额:
$ 36.06万 - 项目类别:
P-GLYCOPROTEIN EXPRESSION AND FUNCTION IN HIV+ WOMEN
HIV 女性中 P-糖蛋白的表达和功能
- 批准号:
6660135 - 财政年份:2002
- 资助金额:
$ 36.06万 - 项目类别:
Pharmacokinetic interactions: digoxin /grapefruit juice
药代动力学相互作用:地高辛/葡萄柚汁
- 批准号:
6566746 - 财政年份:2001
- 资助金额:
$ 36.06万 - 项目类别:
EFFECT OF INTESTINAL TRANSPORTERS ON BIOAVAILABILITY OF DIURETIC FUROSEMIDE
肠道转运蛋白对利尿剂呋塞米生物利用度的影响
- 批准号:
6566772 - 财政年份:2001
- 资助金额:
$ 36.06万 - 项目类别:
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