Ontogeny of drug transport

项目总结 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，这是 包括开发药物转运体和药物代谢酶的表型生物标记物，以及儿科 基于生理的药物动力学(PBPK)模型。在上一个资助期内，我们获得了 对年龄相关的肝脏代谢和从新生儿到成人的转运有相当的了解，这是 被用来建立PBPK模型来预测肝素清除的儿科药物的处置。然而， 对于另一个关键的药物消除器官：肾脏，个体发育数据仍然有限。这项工作的主要目标是 建议定义药物在肾脏中的个体发育。填补这一知识缺口至关重要，因为 大约30%的处方药主要通过肾脏清除，包括几种药物 给儿童开的处方。此外，管状分泌物在儿童戒毒中起着至关重要的作用，这是 通常受限速的有机阴离子或阳离子转运体(分别为燕麦和OCTs)的调控。虽然 我们和其他人最近在存档的肾组织样本中量化了临床相关的药物转运体，这些 数据是高度多变的，而且来自有限数量的受试者，因此无法对 转运体个体发生学。为了解决这些知识差距，我们假设内源底物 血和尿中燕麦和OCT可作为肾脏转运蛋白的非侵入性替代标志物 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：建立健全的 受控临床药物相互作用中成人肾脏燕麦和OCT转运活性的生物标志物 分别以速尿和二甲双胍为探针药物进行研究。燕麦和OCT对OCT的抑制作用 将分别测定外源性和内源性探针上的丙磺舒和西咪替丁。目标 2A：证实燕麦和OCT转运蛋白生物标志物在预测肾转运蛋白个体发育中的作用 Spraogue-Dawley大鼠的丰度和活动性。目的2b：研究大鼠肾脏转运体的个体发育 使用外源性(速尿和二甲双胍)和内源性(生物标志物)肾探针的人 传送者。目的3a：体外研究肾摄取生物标志物的选择性。目标3b：发展和 验证儿童和成人肾分泌阴离子和阳离子药物的生物标志物信息的PBPK模型。 总体而言，这一创新项目将建立非侵入性生物标志物，可用于预测转运体- 儿童和成人的介导的肾脏分泌和药物相互作用潜力。具体地说， 外源性或内源性毒素(如药物或尿毒症)的研究药物对肾脏转运体的抑制作用 毒素)可以使用这些生物标志物在儿童和成人中进行预测。经过验证的传输器活动 从这个翻译项目中获得的生物标记物将为精确剂量的儿科药物提供信息 肾脏在临床试验和临床应用中。

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.