Human Cytochrome P450 4F Enzymes and Drug Interactions

人类细胞色素 P450 4F 酶和药物相互作用

• 批准号: 8507489
• 负责人: Zhuo Michael Wang
• 金额: $ 22.46万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-06 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507489
• 关键词: Address; Adverse event; Anticoagulants; Anticoagulation; Arachidonic Acids; Biological Assay; Catabolism; Cells; Cholesterol; Clinical; Clinical Research; Cytochrome P450; Development; Dose; Double-Blind Method; Drug Interactions; Drug Kinetics; Enzymes; Exhibits; Foundations; Future; Genetic Crossing Over; Goals; Hemorrhage; Hepatocyte; High Pressure Liquid Chromatography; Human; Hydroxylation; In Vitro; Inflammatory; Laboratories; Leukotriene B4; Lovastatin; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolism; Methodology; Methods; Molecular; Nutrient; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Physiological; Placebo Control; Play; Prevalence; Principal Investigator; Property; Proteins; Proteomics; Public Health; Randomized; Recombinants; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Testing; Time; Translational Research; Vitamin E; Vitamin K; Vitamin K 1; Warfarin; Work; base; carboxylation; clinically relevant; clinically significant; cofactor; dosage; gamma-glutamyl carboxylase; healthy volunteer; high risk; improved; innovation; novel; programs; protein expression; public health relevance; tandem mass spectrometry; therapeutic target

DESCRIPTION (provided by applicant): Drug-drug interactions play an important role in clinical adverse events due to the wide prevalence of multi-drug therapies. The human cytochrome P450 4F (CYP4F) subfamily of enzymes has recently been demonstrated to play a significant role in the metabolism of both endogenous compounds, including arachidonic acid and leukotrienes B4 (LTB4), and drugs/nutrients, including pafuramidine, fingolimod, and vitamin E. However, the role of CYP4F enzymes in mediating potential drug interactions remains uncharacterized. Numerous clinically significant adverse interactions, including major and fatal bleeding episodes, have been reported between the widely-prescribed cholesterol-lowering agents, the "statins", and the anticoagulant warfarin. Co-administration of these drugs is expected to be on the rise due in part to the purported pleiotropic effects of statins. An improved understanding of the molecular mechanisms underlying the statin-warfarin interaction will provide necessary scientific basis and methodologies to develop an interaction-free statin-warfarin combination, and allow enactment of pertinent regulatory measures limiting certain high-risk statin-warfarin combinations to be prescribed to hundreds of thousands of people each year, which has great public health importance. The long-term goal of the PI's research program is to further our understanding of the pharmacologic and physiologic roles of the human CYP4F enzymes. The specific goal of the proposed research is to develop a mechanistic understanding of the role of CYP4F2 in the interaction between statins and warfarin. An innovative and translational experimental approach will be employed to test the central hypothesis that certain statins induce CYP4F2-mediated vitamin K1 metabolism and potentiate the anticoagulant effect of warfarin in humans. Novel methodologies, including a mass spectrometry (MS)-based quantitative proteomic approach for protein quantification, a marker substrate activity assay for CYP4F2, and a double-blind, randomized, placebo-controlled, 2-period cross-over clinical study will be utilized to address key issues regarding 1) the deactivation of vitamin K1 upon ?-hydroxylation by CYP4F2; 2) the induction of CYP4F2 protein expression and enzymatic activity by statin treatment; and 3) the clinical relevance of the effect of statins on warfarin anticoagulation efficacy. Results obtained from the proposed translational research will serve as a foundation for understanding the pharmacologic and physiologic role of CYP4F enzymes, and will provide important information useful in the development of safer statins, and a mechanism by which approved statins can be rank-ordered according to their CYP4F2-inducing potential to guide warfarin dosage adjustment when administered concomitantly. The proposed work has the following specific aims: 1) identify and characterize the vitamin K1 metabolite (K1-?-OH) generated by CYP4F2; 2) determine the induction profiles of statins towards CYP4F2 in HepG2 cells and primary human hepatocytes; and 3) assess the influence of statin treatment on the anticoagulant effect of warfarin in healthy volunteers.

描述（由申请人提供）：由于多药疗法的流行，药物 - 药物相互作用在临床不良事件中起着重要作用。 The human cytochrome P450 4F (CYP4F) subfamily of enzymes has recently been demonstrated to play a significant role in the metabolism of both endogenous compounds, including arachidonic acid and leukotrienes B4 (LTB4), and drugs/nutrients, including pafuramidine, fingolimod, and vitamin E. However, the role of CYP4F enzymes in mediating potential药物相互作用仍然没有表征。据报道，广泛规定的降低胆固醇的剂，“他汀类药物”和抗凝华法林之间，已经报道了许多临床上显着的不良相互作用，包括重大和致命的出血发作。预计这些药物的共同给药会因他汀类药物的多效性作用而有所增加。对他汀类药物 - 瓦素相互作用的分子机制的改进理解将提供必要的科学依据和方法，以开发与无毒性的他汀类药物 - 瓦尔法林组合，并允许对相关的监管措施实施限制某些高风险的他汀类药物毒素 - 毒素 - 毒蛋白 - 毒素组合，以使其每年都有很高的公共健康状况，以使其每年都有很高的公共健康。 PI研究计划的长期目标是进一步了解人类CYP4F酶的药理和生理作用。拟议的研究的具体目标是对CYP4F2在他汀类药物与华法林之间相互作用中的作用有一种机械理解。将采用一种创新的转化实验方法来检验某些他汀类药物诱导CYP4F2介导的维生素K1代谢并增强华法林对人类的抗凝作用的中心假设。新的方法论，包括用于蛋白质定量的质谱（MS）定量蛋白质组学方法，CYP4F2的标记底物活性测定以及一项双盲，随机，随机，安慰剂对照，2-周期交叉临床研究将通过1）依赖于1）基于1）的关键问题。 2）通过他汀类药物治疗诱导CYP4F2蛋白表达和酶促活性； 3）他汀类药物对华法林抗凝功效的影响的临床相关性。从拟议的翻译研究中获得的结果将成为理解CYP4F酶的药理和生理作用的基础，并将提供对开发更安全的汀类药物的开发的重要信息，以及一种机制，通过该机制可以根据CYP4F2的潜在来指导WARFARAIN供应剂量调整时，可以通过批准的statins订购。拟议的工作具有以下特定目的：1）识别和表征CYP4F2产生的维生素K1代谢产物（K1 - ？ - OH）； 2）确定他汀类药物对HEPG2细胞和原代人肝细胞中CYP4F2的诱导谱； 3）评估他汀类药物治疗对华法林在健康志愿者中抗凝作用的影响。