Genomic and drug-drug interaction mechanisms of interindividual variability in drug disposition

药物处置个体差异的基因组和药物相互作用机制

基本信息

批准号：
10406564
负责人：
Zeruesenay Desta
金额：
$ 39.63万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10406564
关键词：
Adverse drug effect Adverse effects Bupropion CYP1A2 gene CYP2B6 gene CYP2D6 gene Caliber Clinical Complement Complex Development Diastolic blood pressure Dose Drug Exposure Drug Interactions Drug Kinetics Enzymes Extrahepatic Funding Genetic Genetic Variation Genomics Genotype Goals Guidelines HIV Hepatic Human In Vitro Inherited Intestines Kidney Kinetics Knowledge Liver Metabolic Pathway Metabolism Methadone Methods Microsomes National Institute of General Medical Sciences Package Insert Paper Patients Persons Pharmaceutical Preparations Pharmacotherapy Positioning Attribute Public Health Publications Pupil Research Risk Role Science Stereoisomer Testing Tissues Toxic effect UGT1A1 gene Variant Work base clinical phenotype differential expression drug disposition drug efficacy drug metabolism efavirenz genetic makeup genomic biomarker healthy volunteer in silico in vivo inter-individual variation liquid chromatography mass spectrometry medication safety novel personalized medicine precision drugs response tizanidine tool

项目摘要

Project Summary/Abstract Large degree of interindividual variability in drug response frequently compromises drug safety and efficacy. The long-term goal of my research is a mechanistic and clinical understanding of this variability and then personalized drug therapy. My research, funded mainly by NIGMS, has focused on the changes in drug pharmacokinetics due to both 1) inherited differences in drug disposition and 2) unpredictable drug-drug interactions (DDIs). This work produced new and novel mechanisms of drug disposition and identified genetic and DDI factors responsible for interindividual variability in drug and/or active metabolite exposure and effects. Novel in vitro and clinical phenotyping tools, genomic biomarkers and LC/MS/MS methods were developed that significantly advanced the science of drug disposition and stimulated collaborative and worldwide research endeavors. Examples include revision of the FDA package insert for efavirenz, development of dosing guidelines and position papers on efavirenz and CYP2B6, and the use of efavirenz as in vitro and in vivo probe of CYP2B6 activity. Yet, incomplete understanding of the mechanisms for interindividual variability in drug disposition persists for many other clinically important drugs and continues to compromise the implementation of maximum drug efficacy with minimal toxicity. This knowledge gap is the focus of this MIRA application. 1) The combined effect of genetic variability in drug disposition and DDIs on drug exposure and effect has rarely been studied. Efavirenz (a CYP2B6 substrate and a critical drug for the treatment of HIV) induces hepatic CYP2B6 and inhibits hepatic CYP1A2 in CYP2B6 genotype-dependent fashion. We hypothesize that interplay of genetic variations and DDIs is a key driver of intersubject differences in drug disposition and effect. In healthy volunteers genotyped for CYP2B6 variants, the stereoselective disposition and effect (e.g., pupil diameter) of methadone (a CYP2B6 substrate) and the disposition and effect (systolic and diastolic blood pressures) of tizanidine (a sensitive CYP1A2 substrate) will be determined at baseline and after pretreatment with efavirenz (600 mg/day PO for 17 days). 2) UGTs are differentially expressed in extrahepatic tissues, but their role in in drug metabolism is incompletely understood. Building on our recent publication with dolutegravir (a UGT1A1 and UGT1A9 substrate), we will test the hypothesis that modulation of extrahepatic metabolism of UGT substrates contributes to the variability in exposure of UGT substrates. In-depth in vitro kinetic and inhibition studies will be performed in microsomes derived from UGT genotyped human hepatic, intestinal and kidney tissues. 3) Some clinically observed complex DDIs are unpredictable based on current knowledge. Capitalizing on our work with bupropion-CYP2D6 interaction, in vitro DDI studies are proposed to identify the mechanistic basis of clinically observed DDIs, focusing on circulating metabolites/stereoisomers and less well- understood metabolic pathways. Appropriate in silico approaches will complement our studies. The results will enhance our ability to personalize drug therapy.

项目摘要/摘要药物反应的大大个体差异经常损害药物安全性和功效。我研究的长期目标是对这种可变性和然后个性化的药物疗法。我的研究主要由Nigms资助，重点是药物的变化两种药物的药代动力学。1）药物处置的遗传差异和2）不可预测的药物药物相互作用（DDI）。这项工作产生了新的新型药物处置机制，并确定了遗传和DDI因素，导致药物和/或主动代谢物暴露和影响的个体变异性。开发了新型体外和临床表型工具，基因组生物标志物和LC/MS/MS方法这显着推动了药物处置科学的发展，并刺激了协作和全球研究努力。示例包括修订Efavirenz的FDA软件包插入物，剂量的开发关于efavirenz和CYP2B6的指南和位置论文，以及Efavirenz作为体外和体内探针的使用 CYP2B6活性。然而，对药物间个体变异的机制不完全理解对许多其他临床上重要的药物的处置仍然存在，并继续损害实施最大的药物功效，最小的毒性。这种知识差距是此MIRA应用的重点。 1）遗传变异性在药物处置和DDI对药物暴露和影响的综合作用已很少被研究。 efavirenz（CYP2B6底物和艾滋病毒治疗的关键药物）诱导肝CYP2B6并以CYP2B6基因型依赖性方式抑制肝CYP1A2。我们假设遗传变异和DDIS的相互作用是药物处置差异的关键驱动力和影响。在针对CYP2B6变体的健康志愿者基因分型中，立体选择性和效果（例如，美沙酮（CYP2B6底物）的瞳孔直径）和处置和作用（收缩和舒张血 Tizanidine的压力（敏感CYP1A2底物）将在基线和预处理后确定与efavirenz（600 mg/day PO持续17天）。 2）UGT在肝外组织中差异表达，但它们在药物代谢中的作用尚不完全理解。在我们最近与Dolutegravir出版的基础上（ugt1a1和ugt1a9底物），我们将测试以下假设。 UGT底物有助于UGT底物暴露的变化。深入的体外动力学和抑制研究将在源自UGT基因分型人肝，肠和肠道的微粒体中进行肾脏组织。 3）基于当前知识，一些临床上观察到的复杂DDI是不可预测的。利用我们通过安非他酮-CYP2D6相互作用的工作，提出了体外DDI研究以识别临床观察到的DDI的机械基础，专注于循环代谢物/立体异构体，较少的良好理解的代谢途径。在计算机方法中适当的方法将补充我们的研究。结果将增强我们个性化药物治疗的能力。