参与肝内循环的药物转运体和共轭酶的发育表达:对儿科药物剂量的影响

IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Clinical Pharmacology & Therapeutics Pub Date : 2024-08-19 DOI:10.1002/cpt.3409
Aarzoo Thakur, Sandhya Subash, Deepak Ahire, Bhagwat Prasad
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引用次数: 0

摘要

用于儿童的药物中约有 50%从未在这一弱势群体中进行过安全性和有效性测试。如果采用体表面积或体重归一化成人剂量等经验方法确定儿科剂量,不成熟的药物消除途径可能会导致药物毒性。在缺乏临床数据的情况下,基于生理学的药代动力学(PBPK)模型已成为预测儿童药物药代动力学的有用工具。这些模型利用发育生理数据,包括药物代谢酶和转运体(DMET)丰度随年龄的差异,从机理上将成人药代动力学数据外推至儿童。已报道的从冷冻组织中分离的亚细胞分馏物中肝脏 DMET 蛋白的丰度数据容易产生较大的技术变异。因此,我们对 50 个儿童和 8 个成人肝细胞样本中的肝脏药物转运体和结合酶进行了基于蛋白质组学的定量分析。在研究的 34 种蛋白质中,有 28 种随着年龄的增长而明显增加或减少。而 MRP6、OAT7 和 SULT1E1 在小儿和成人肝细胞中的含量最高。
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Developmental Expression of Drug Transporters and Conjugating Enzymes Involved in Enterohepatic Recycling: Implication for Pediatric Drug Dosing.

Around 50% of the drugs used in children have never been tested for safety and efficacy in this vulnerable population. Immature drug elimination pathways can lead to drug toxicity when pediatric doses are determined using empirical methods such as body-surface area or body-weight-normalized adult dosing. In the absence of clinical data, physiologically-based pharmacokinetic (PBPK) modeling has emerged as a useful tool to predict drug pharmacokinetics in children. These models utilize developmental physiological data, including age-dependent differences in the abundance of drug-metabolizing enzymes and transporters (DMET), to mechanistically extrapolate adult pharmacokinetic data to children. The reported abundance data of hepatic DMET proteins in subcellular fractions isolated from frozen tissue are prone to high technical variability. Therefore, we carried out the proteomics-based quantification of hepatic drug transporters and conjugating enzymes in 50 pediatric and 8 adult human hepatocyte samples. Out of the 34 studied proteins, 28 showed a significant increase or decrease with age. While MRP6, OAT7, and SULT1E1 were highest in < 1-year-old samples, the abundance of P-gp and UGT1A4 was negligible in < 1-year-old samples and increased significantly after 1 year of age. Incorporation of the age-dependent abundance data in PBPK models can help improve pediatric dose prediction, leading to safer drug pharmacotherapy in children.

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来源期刊
CiteScore
12.70
自引率
7.50%
发文量
290
审稿时长
2 months
期刊介绍: Clinical Pharmacology & Therapeutics (CPT) is the authoritative cross-disciplinary journal in experimental and clinical medicine devoted to publishing advances in the nature, action, efficacy, and evaluation of therapeutics. CPT welcomes original Articles in the emerging areas of translational, predictive and personalized medicine; new therapeutic modalities including gene and cell therapies; pharmacogenomics, proteomics and metabolomics; bioinformation and applied systems biology complementing areas of pharmacokinetics and pharmacodynamics, human investigation and clinical trials, pharmacovigilence, pharmacoepidemiology, pharmacometrics, and population pharmacology.
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