Drug Interactions

药物相互作用

• 批准号: 8334087
• 负责人: Allan Edward Rettie
• 金额: $ 137.97万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334087
• 关键词: Address; Amiodarone; Amprenavir; Anticoagulants; Automation; Behavior; Biological; Biological Assay; Biological Models; Blood - brain barrier anatomy; Blood capillaries; Budgets; CYP3A4 gene; Carbamazepine; Cell model; Chemicals; Clinical; Collaborations; Complex; Concept Formation; Cytochrome P450; Cytochromes b5; Data; Data Collection; Deuterium; Development; Diltiazem; Drug Combinations; Drug Interactions; Drug Kinetics; Elements; Enzymes; Event; Expenditure; Faculty; Fluoxetine; Funding; Future; Genes; Genetic Polymorphism; Genotype; Grant; Hepatocyte; Human; Hydroxylamine; Image; In Vitro; Individual; Institution; Ions; Itraconazole; Kinetics; Laboratories; Liver; Maps; Mass Spectrum Analysis; Medicine; Methodology; Methods; Midazolam; Molecular; Monitor; Oral; P-Glycoprotein; Peptides; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacy Schools; Plasma; Play; Principal Investigator; Program Research Project Grants; Proteins; Publications; Publishing; Quinidine; Quinine; Reporting; Research; Research Personnel; Resolution; Resource Sharing; Resources; Rodent; Role; Sampling; Scanning; Sensitivity and Specificity; Students; System; Techniques; Technology; Testing; Time; Tissue Banking; Tissue Banks; Travel; Universities; Warfarin; Washington; Water; base; capillary; crosslink; human tissue; improved; in vivo; innovation; instrument; instrumentation; ionization; mass spectrometer; meetings; nile red; novel; operation; programs; research study; selected ion monitoring; stable isotope; translational study; urinary

This interdisciplinary program project grant involves four highly collaborative projects and three Core elements involving faculty from five departments of the Schools of Pharmacy and Medicine of the University of Washington and collaboration with two other institutions. Collectively, it is focused (i) on understanding molecular mechanisms that complicate prediction of drug-drug interactions from in vitro data, and (ii) developing methods to allow the prediction of such events from in vitro experiments before humans are exposed to dangerous combinations of drugs in vivo. Project 1 will define the influence of genotype on the magnitude of inhibitory and inductive drug-drug interactions involving the oral anticoagulant drug, warfarin. This information can guide management of warfarin drug interactions in carriers of common polymorphisms within genes controlling the pharmacokinetics and pharmacodynamics of the drug. Interactions involving alkylamine drugs are often complicated by time-dependent inhibition of P450s through formation of a metabolite-intermediate (Ml) complex. Project 2 is pioneering the concept that formation of secondary hydroxylamine metabolites of alkylamine drugs are the pivotal step in Ml complex formation in vitro and in vivo. Extrapolating from in vitro kinetic data to the in vivo situation is further complicated by the phenomenon of P450 allosterism. Project 3 is studying the mechanistic underpinning for activation kinetics among human P450s and will also test if such allosteric behavior occurs in vivo. Finally, Project 4 addresses the quantitative prediction of P-glycoprotein based drug-drug interactions at the human blood-brain barrier These studies are possible because of novel and innovative imaging methodologies developed by this project that will be used combination with cell model systems and rodent studies.

这个跨学科计划项目赠款涉及四个高度合作的项目和三个核心要素，涉及华盛顿大学药学院和医学院五个系的教师，并与其他两个机构合作。总的来说，它的重点是（i）了解复杂的预测药物相互作用的体外数据的分子机制，和（ii）开发方法，允许预测这些事件在体外实验之前，人类暴露于危险的药物组合在体内。项目1将确定基因型对口服抗凝药物华法林的抑制性和诱导性药物相互作用的影响。 这些信息可以指导华法林药物相互作用在控制药物药代动力学和药效学的基因内的常见多态性载体中的管理。涉及烷基胺药物的相互作用通常由于通过形成代谢物-中间体（MI）复合物对P450的时间依赖性抑制而复杂化。项目2开创了烷基胺药物的仲羟胺代谢物的形成是体外和体内Ml复合物形成的关键步骤的概念。P450变构现象使从体外动力学数据外推到体内情况进一步复杂化。项目3正在研究人类P450激活动力学的机制基础，并将测试这种变构行为是否在体内发生。最后，项目4提出了定量预测P-糖蛋白在人血脑屏障上的药物相互作用 这些研究是可能的，因为该项目开发的新颖和创新的成像方法，将与细胞模型系统和啮齿动物研究相结合。

项目成果

Racemates versus enantiomers in drug development: dogmatism or pragmatism?

• DOI: 10.1002/chir.530020302
• 发表时间: 1990
• 期刊: Chirality
• 影响因子: 2
• 作者: B. Testa;W. Trager

Functional analysis of phenylalanine residues in the active site of cytochrome P450 2C9.

• DOI: 10.1021/bi801231m
• 发表时间: 2008-11-11
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Mosher, Carrie M.;Hummel, Matthew A.;Tracy, Timothy S.;Rettie, Allan E.
• 通讯作者: Rettie, Allan E.

(R)-(+)-Menthofuran is a potent, mechanism-based inactivator of human liver cytochrome P450 2A6.

• 发表时间: 1998-07
• 期刊: Drug metabolism and disposition: the biological fate of chemicals
• 作者: S. Khojasteh-Bakht;L. Koenigs;Raimund M. Peter;William Trager;Sidney D. Nelson

Inhibition-based metabolic drug-drug interactions: predictions from in vitro data.

• DOI: 10.1002/jps.10179
• 发表时间: 2002-09
• 期刊: Journal of pharmaceutical sciences
• 影响因子: 3.8
• 作者: C. Yao;R. Levy

First-pass midazolam metabolism catalyzed by 1alpha,25-dihydroxy vitamin D3-modified Caco-2 cell monolayers.

1α,25-二羟基维生素 D3 修饰的 Caco-2 细胞单层催化首过咪达唑仑代谢。

• 发表时间: 1999
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Fisher,JM;Wrighton,SA;Watkins,PB;Schmiedlin-Ren,P;Calamia,JC;Shen,DD;Kunze,KL;Thummel,KE
• 通讯作者: Thummel,KE