Ontogeny of drug transport

药物转运的个体发育

• 批准号: 10675572
• 负责人: Bhagwat Prasad
• 金额: $ 60.48万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675572
• 关键词: 17 year old; Acyclovir; Address; Adult; Aminoglycosides; Animals; Anions; Archives; Avena sativa; Biological Markers; Blood; Body Surface Area; Body Weight; Cations; Cell Line; Child; Childhood; Cimetidine; Cisplatin; Clinic; Clinical; Clinical Research; Clinical Trials; Data; Dose; Drug Interactions; Drug Kinetics; Drug Metabolic Detoxication; Drug Prescriptions; Drug Transport; Drug toxicity; Drug usage; Enzymes; Excretory function; Funding; Furosemide; Goals; Grant; Growth; Half-Life; Health Benefit; Hepatic; Human; In Vitro; Individual; Infant; Investigational Drugs; Kidney; Knowledge; Liver; Measures; Mediating; Metformin; Methods; Organ; Peer Review; Pharmaceutical Preparations; Phase II Clinical Trials; Physiological; Physiology; Play; Population; Probenecid; Process; Proteins; Proteomics; Public Health; Rattus; Renal clearance function; Renal function; Reporting; Role; Sprague-Dawley Rats; Surrogate Markers; Testing; Tissue Sample; Toxic effect; Toxin; Tubular formation; United States Food and Drug Administration; Uremia; Urine; Validation; Vancomycin; Xenobiotics; age related; biomarker development; biomarker panel; biomarker validation; clinical development; clinically relevant; drug disposition; glomerular filtration; innovation; liver metabolism; metabolomics; model development; neonate; nephrotoxicity; novel; novel marker; off-label use; pediatric drug development; pharmacokinetic model; phenotypic biomarker; predictive marker; preterm newborn; prevent; response; toxicant; uptake

PROJECT SUMMARY Our long-term goal is to establish non-invasive approaches to predict drug disposition in children, which includes developing phenotypic biomarkers of drug transporters and drug metabolizing enzymes and pediatric physiologically-based pharmacokinetic (PBPK) models. During the previous funding period, we gained a considerable understanding of age-dependent hepatic metabolism and transport from neonates to adults, which was used to develop PBPK models to predict the disposition of hepatically cleared pediatric drugs. However, ontogeny data remain limited for another key drug elimination organ: the kidney. The main objective of this proposal is to define the ontogeny of drug transport in the kidney. Filling this knowledge gap is critical, as approximately 30% of prescription drugs are cleared predominantly by the kidneys, including several drugs prescribed to children. Further, tubular secretion plays a crucial role in drug detoxification in children, which is often regulated by the rate-limiting organic anion or cation transporters (OATs and OCTs, respectively). Although we and others recently quantified clinically relevant drug transporters in archived kidney tissue samples, these data are highly variable and are from a limited number of subjects, precluding a meaningful interpretation of transporter ontogeny. To address these knowledge gaps, we hypothesize that endogenous substrates of OATs and OCTs in blood and urine can be used as surrogate, non-invasive markers of kidney transporter function in children and adults. We will test this hypothesis via three Specific Aims. Aim 1: Establish robust biomarkers of renal OAT and OCT transport activity in adult humans in a controlled clinical drug-drug interaction study using furosemide and metformin as probe drugs, respectively. The effects of OAT and OCT inhibition by probenecid and cimetidine, respectively, on both exogenous and endogenous probes will be determined. Aim 2a: Confirm the utility of Oat and Oct transporter biomarkers in predicting ontogeny of renal transporter abundance and activity in Sprague-Dawley rats. Aim 2b: Characterize the ontogeny of renal transporters in humans using exogenous (furosemide and metformin) and endogenous (biomarkers) probes of renal transporters. Aim 3a: Characterize the selectivity of renal uptake of the biomarkers in vitro. Aim 3b: Develop and validate biomarker-informed PBPK models for renally secreted anionic and cationic drugs in children and adults. Collectively, this innovative project will establish non-invasive biomarkers that can be used to predict transporter- mediated renal secretion and drug-drug interaction potential in children and adults. Specifically, the effect of inhibition of renal transporters by an investigational drug on xenobiotic or endobiotic toxins (e.g., drugs or uremic toxins) can be predicted in children and adults using these biomarkers. The validated transporter activity biomarkers garnered from this translational project will inform precision dosing of pediatric drugs secreted by kidneys during clinical trials and clinical use.

项目概要 我们的长期目标是建立非侵入性方法来预测儿童的药物处置，这 包括开发药物转运蛋白和药物代谢酶的表型生物标志物以及儿科药物 基于生理的药代动力学（PBPK）模型。在之前的融资期间，我们获得了 对年龄依赖性肝脏代谢和从新生儿到成人的运输有深入的了解，这 用于开发 PBPK 模型来预测肝清除儿科药物的处置。然而， 另一个关键的药物消除器官：肾脏的个体发育数据仍然有限。此举的主要目标 建议是定义肾脏中药物转运的个体发育。填补这一知识空白至关重要，因为 大约 30% 的处方药主要由肾脏清除，包括几种药物 规定给儿童。此外，肾小管分泌在儿童药物解毒中起着至关重要的作用，这是 通常由限速有机阴离子或阳离子转运蛋白（分别为 OAT 和 OCT）调节。虽然 我们和其他人最近量化了存档的肾组织样本中的临床相关药物转运蛋白，这些 数据变化很大，并且来自有限数量的受试者，因此无法对数据进行有意义的解释 转运体个体发育。为了解决这些知识差距，我们假设内源底物 血液和尿液中的 OAT 和 OCT 可用作肾脏转运蛋白的替代、非侵入性标记物 在儿童和成人中发挥作用。我们将通过三个具体目标来检验这一假设。目标 1：建立稳健的 在受控临床药物相互作用中成人肾 OAT 和 OCT 转运活性的生物标志物 分别使用呋塞米和二甲双胍作为探针药物的研究。 OAT 和 OCT 抑制作用 将分别测定外源性和内源性探针上的丙磺舒和西咪替丁。目的 2a：确认燕麦和 Oct 转运蛋白生物标志物在预测肾转运蛋白个体发育中的效用 Sprague-Dawley 大鼠中的丰度和活性。目标 2b：表征肾转运蛋白的个体发育 人类使用外源性（呋塞米和二甲双胍）和内源性（生物标志物）肾探针 运输者。目标 3a：表征肾脏体外摄取生物标志物的选择性。目标 3b：开发和 验证儿童和成人肾分泌阴离子和阳离子药物的基于生物标志物的 PBPK 模型。 总的来说，这个创新项目将建立非侵入性生物标志物，可用于预测转运蛋白 介导儿童和成人的肾脏分泌和药物相互作用潜力。具体来说，效果是 通过针对外源性或内源性毒素的研究药物（例如药物或尿毒症药物）抑制肾脏转运蛋白 使用这些生物标志物可以预测儿童和成人的毒素）。经验证的转运蛋白活性 从这个转化项目中获得的生物标志物将指导儿童分泌的药物的精确剂量 临床试验和临床使用期间的肾脏。

项目成果

Ontogeny of Drug-Metabolizing Enzymes.

• DOI: 10.1007/978-1-0716-1554-6_18
• 发表时间: 2021
• 期刊: Methods in molecular biology
• 作者: Aarzoo Thakur;M. Parvez;J. Leeder;B. Prasad

Proteomics-informed physiologically-based pharmacokinetic (PBPK) modeling revealed differential effects of UGT2B17 variability on the pharmacokinetics of diclofenac following intravenous and oral administration.

基于蛋白质组学的生理药代动力学 (PBPK) 模型揭示了 UGT2B17 变异性对静脉和口服给药后双氯芬酸药代动力学的不同影响。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Ahire,DeepakS;Prasad,Bhagwat
• 通讯作者: Prasad,Bhagwat

Impact of CYP2C:TG Haplotype on CYP2C19 Substrates Clearance In Vivo, Protein Content, and In Vitro Activity.

CYP2C:TG 单倍型对 CYP2C19 体内底物清除率、蛋白质含量和体外活性的影响。

• DOI: 10.1002/cpt.3012
• 发表时间: 2023
• 期刊: Clinical pharmacology and therapeutics
• 影响因子: 6.7
• 作者: Zubiaur,Pablo;Soria-Chacartegui,Paula;Boone,ErinC;Prasad,Bhagwat;Dinh,Jean;Wang,WendyY;Zugbi,Santiago;Rodríguez-Lopez,Andrea;González-Iglesias,Eva;Leeder,JSteven;Abad-Santos,Francisco;Gaedigk,Andrea
• 通讯作者: Gaedigk,Andrea

Ontogeny of Hepatic Drug Transporters as Quantified by LC-MS/MS Proteomics.

• DOI: 10.1002/cpt.409
• 发表时间: 2016-10
• 期刊: Clinical pharmacology and therapeutics
• 影响因子: 6.7
• 作者: Prasad B;Gaedigk A;Vrana M;Gaedigk R;Leeder JS;Salphati L;Chu X;Xiao G;Hop C;Evers R;Gan L;Unadkat JD
• 通讯作者: Unadkat JD

Targeted LC-MS/MS Proteomics-Based Strategy To Characterize in Vitro Models Used in Drug Metabolism and Transport Studies.

• DOI: 10.1021/acs.analchem.8b01913
• 发表时间: 2018-10-16
• 期刊: Analytical chemistry
• 影响因子: 7.4
• 作者: Xu M;Saxena N;Vrana M;Zhang H;Kumar V;Billington S;Khojasteh C;Heyward S;Unadkat JD;Prasad B
• 通讯作者: Prasad B