大鼠和人类肝脏有机阳离子转运体-1的本体发育

IF 4.4 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Sarinj Fattah, Abhijit Babaji Shinde, Myriam Baes, Karel Allegaert, Patrick Augustijns, Pieter Annaert
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引用次数: 0

摘要

有机阳离子转运体-1(OCT1)介导肝脏对阳离子内源性化合物和异种生物的吸收。迄今为止,关于大鼠和人类肝脏中 Oct1/OCT1 的功能如何随着年龄的增长而发展,以及这将如何影响儿童或幼年动物体内 OCT 底物的药代动力学的信息还很有限。通过测定作为已知 rOct/hOCT 探针底物的 4-[4-(二甲基氨基)苯乙烯基]-N-甲基吡啶鎓碘化物(ASP+)的摄取清除率,对悬浮大鼠(2-57 天大)和人类肝细胞(儿科肝脏组织供体:2-12 个月大)中 rOct/hOCT 的功能发育进行了剖析。mRNA 表达在与功能研究中使用的大鼠年龄相对应的大鼠肝组织中进行测定,而 hOCT1 mRNA 表达则在用于摄取研究的相同批次肝细胞中进行测定。rOct/hOCT 活性和表达的成熟度是通过比较不同年龄段获得的值与成年值来评估的。相对于成年值(8 周),0、1、2、3、4、5 和 6 周龄的悬浮大鼠肝细胞中 ASP+ 的摄取清除率分别达到 26%、29%、33%、37%、72%、63% 和 71%。肝脏 Oct1 mRNA 表达与 Oct 活性一致(相关系数为 0.92)。在人类肝细胞中,OCT1 活性与年龄有关,也与 mRNA 水平相关(相关系数为 0.88)。这些数据表明,Oct1/OCT1 的活性和表达在大鼠/人类肝脏中逐渐成熟,从而反映了有机阴离子转运多肽(Oatp1b2)在大鼠中的表达模式。这些高分辨率的转运体本体图谱将有助于更准确地预测 OCT1/Oct1 底物在儿科人群和幼年动物中的药代动力学。意义声明 有机阳离子转运体-1(OCT1)是人类肝脏中主要的药物摄取转运体。本研究以大鼠和人类肝细胞的体外实验为基础,提供了有关肝脏中 OCT1 功能随年龄变化的高分辨率数据。这些本体特征将为改进新生儿、婴儿、儿童和成人中 OCT1 药物底物的特定年龄生理药代动力学(PBPK)模型提供依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ontogeny of Hepatic Organic Cation Transporter-1 in Rat and Human.

The organic cation transporter (OCT)-1 mediates hepatic uptake of cationic endogenous compounds and xenobiotics. To date, limited information exists on how Oct1/OCT1 functionally develops with age in rat and human livers and how this would affect the pharmacokinetics of OCT substrates in children or juvenile animals. The functional ontogeny of rOct/hOCT was profiled in suspended rat (2-57 days old) and human hepatocytes (pediatric liver tissue donors: age 2-12 months) by determining uptake clearance of 4-[4-(dimethylamino)styryl]-N-methylpyridinium iodide (ASP+) as a known rOct/hOCT probe substrate. mRNA expression was determined in rat liver tissue corresponding to rat ages used in the functional studies, while hOCT1 mRNA expressions were determined in the same hepatocyte batches as those used for uptake studies. Maturation of rOct/hOCT activity and expression were evaluated by comparing values obtained at the various ages to the adult values. Relative to adult values (at 8 weeks), ASP+ uptake clearance in suspended rat hepatocytes aged 0, 1, 2, 3, 4, 5, and 6 weeks reached 26%, 29%, 33%, 37%, 72%, 63%, and 71%, respectively. Hepatic Oct1 mRNA expression was consistent with Oct activity (correlation coefficient of 0.92). In human hepatocytes, OCT1 activity was age dependent and also correlated with mRNA levels (correlation coefficient of 0.88). These data show that Oct1/OCT1 activities and expression mature gradually in rat/human liver, thereby mirroring the expression pattern of organic anion transporting polypeptide in rat. These high-resolution transporter ontogeny profiles will allow for more accurate prediction of the pharmacokinetics of OCT1/Oct1 substrates in pediatric populations and juvenile animals. SIGNIFICANCE STATEMENT: Organic cation transporter-1 (OCT1) represents a major drug uptake transporter in human liver. This study provides high-resolution data regarding the age-dependent function of OCT1 in the liver, based on in vitro experiments with rat and human hepatocytes obtained from donors between birth and adulthood. These ontogeny profiles will inform improved age-specific physiologically based pharmacokinetic models for OCT1 drug substrates in neonates, infants, children, and adults.

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来源期刊
CiteScore
6.50
自引率
12.80%
发文量
128
审稿时长
3 months
期刊介绍: An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.
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