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More Than Pharmacokinetics: Transporters in Clinical Pharmacology
Clinical Pharmacology & Therapeutics ( IF 6.3 ) Pub Date : 2022-08-21 , DOI: 10.1002/cpt.2710
Kathleen M Giacomini 1 , Shiew Mei Huang 2
Affiliation  

Through pharmacokinetic and pharmacodynamics mechanisms, membrane transporters play crucial roles in therapeutic and adverse drug effects (Figure 1). Key transporters that govern the absorption, distribution, and elimination in different organs are listed in Figure 2. Their critical roles in affecting the disposition of endogenous substances and drugs can be delineated using various tools (Figure 3).

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FIGURE 1
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Clinical Pharmacology & Therapeutics September 2022 cover image: Transporters.
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FIGURE 2
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A diagram showing important polyspecific drug transporters in the intestine liver and kidney. Arrows indicate the primary direction of transport, although some of the transporters are bidirectional. The transporters shown are major targets for clinically important drug–drug interactions.4 The figure was created with biorender.com.
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FIGURE 3
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Different omics methodologies and technologies used in the study of transporters in clinical pharmacology. The figure, which was created with biorender.com, is extracted from ref. 3 of this issue of Clinical Pharmacology & Therapeutics.

Included in this theme issue of Clinical Pharmacology & Therapeutics (CPT) are manuscripts co-authored by members of the International Transporter Consortium (ITC), a multisector organization of experts in transporters, which for over a decade has served as a thought leader for transporters at the interface of drug discovery and development,1 researchers from the RESOLUTE consortium,2 a public–private partnership whose mission is to expand worldwide research on solute carriers (SLCs), and a wide range of authors from industry and academic institutions around the world. For example, a manuscript by Brouwer et al., “Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the ITC,”3 describes the key mechanisms and factors, ranging from gene regulation and microRNAs through post-translational modification and trafficking, that regulate the expression and activity of drug transporters in tissues of pharmacologic importance. Regulation of hepatic drug metabolizing enzymes through nuclear receptors (e.g., pregnane X receptor (PXR) mediated enzyme induction), is known to play a major role in interindividual variation in the pharmacokinetics and pharmacodynamics of many drugs. As highlighted by Brouwer et al., some of these same nuclear receptors, for example, PXR and farnesoid X-activated receptor (FXR), are involved in the regulation of hepatic transporters and as such mediate a highly coordinated level of regulation of the genes and proteins involved in xenobiotic elimination (i.e., transporters and enzymes). Tables 2 and 3 of Brouwer et al. present the major mechanisms involved in the regulation of transporters in the intestine and liver and represent key reference materials for clinical pharmacologists seeking to understand the mechanisms involved in interindividual differences in drug absorption and elimination. The manuscript ends with a call for more research to close knowledge gaps in the complex mechanisms involved in regulation of transporters and enzymes involved in drug absorption and elimination.

The call for more research and the application of new technologies to closing knowledge gaps of transporters is echoed in another manuscript, “New and emerging research on SLC and ABC transporters in drug discovery and development: Outlook from the International Transporter Consortium.”4 In this manuscript, the authors describe a wealth of new technologies that has resulted in great advances in research in membrane transporters over the past decade. The authors highlight advances at the basic, translational, and clinical research levels. For example, the application of cryogenic electron microscopy has resulted in a plethora of high-resolution structures of many membrane transporters in both the ATP-Binding Cassette (ABC) superfamily and the SLC superfamily. These structures have greatly enabled the ability to target transporters in drug discovery efforts through molecular docking methods. Translational proteomic research carried out over the last 5 years has led to a quantitative understanding of transporter abundance in various tissues, which in turn has informed physiologically-based pharmacokinetic modeling (PBPK). Advances in clinical research are described, including new clinical tools, such as tissue-derived small extracellular vesicles. These vesicles, which include exosomes derived from particular tissues, express transporters and enzymes and can be used as biomarkers for pharmacokinetics and pharmacodynamics. The manuscript also describes a set of small molecules, such as uric acid and bilirubin, that are commonly present in individual patient health records and can be used as real-world biomarkers of transporter activity and expression. For example, uric acid is a biomarker of BCRP (ABCG2) and bilirubin is a biomarker for OATP1B1 (SLCO1B1).

Biomarkers were introduced as a new area of research in drug transporters in the previous theme issue of transporters published in the November 2018 issue of CPT.5 In 2022, transporter biomarkers are now routinely used in pharmacokinetic and drug–drug interaction studies. In this issue of CPT, several original research articles are focused on transporter biomarkers. Takita et al., in “Coproporphyrin I as an endogenous biomarker to detect reduced OATP1B activity and shift in elimination route in chronic kidney disease,”6 use coproporphyrin I (CPI) levels in the plasma to understand the complex interplay among chronic kidney disease (CKD), hepatic uptake of drugs, and inhibition of hepatic transport by rifampicin, which is more marked in patients with CKD than in healthy volunteers. This elegant study extends PBPK modeling to patients with CKD to detect CKD–drug interaction risks for drugs that are substrates of the liver transporter, OATP1B1, and are also cleared in part by the kidneys. The authors conclude that in CKD, CPI renal elimination virtually disappears resulting in an increased fraction of the endogenous molecule being transported by OATP1B1. Thus, inhibition of OATP1B1 results in a larger effect on the levels of CPI in patients with CKD in comparison to those without renal dysfunction. Similar effects would be expected for drugs that are OATP1B1 substrates and have both renal and hepatic pathways of elimination.

Another intriguing original research article focused on biomarkers comes from the Nigam laboratory, “Blockade of organic anion transport in humans after treatment with the drug probenecid leads to major metabolic alterations in plasma and urine.”7 This manuscript explores the effects of the renal organic anion transporter inhibitor probenecid on plasma and urine levels of endogenous metabolites in 20 healthy volunteers. By measuring both plasma and urine, the investigators can identify endogenous substrates of renal secretory organic anion transporters looking specifically for metabolites that are elevated in plasma but reduced in urine. Interestingly, they find a diverse array of molecules (about 100) including some known gut microbiome products. By using mice that have specific knockouts of organic anion transporter 1 (OAT1, SLC22A6) or organic anion transporter 3 (OAT3, SLC22A8), they validate a subset of the metabolites identified in the probenecid study in healthy volunteers and detect which of the metabolites are specific for each of the two major organic anion transporters. Care in the interpretation of the data is needed because of potential species differences between the mouse and human transporters as well as different pathways of metabolism of endogenous molecules. Nevertheless, this study is consistent with the Remote Sensing and Signaling Theory, which suggests that promiscuous transporters in the SLC22 family are critical determinants of human metabolism.

Finally, the issue includes several interesting perspectives on transporter research. Notably, Giulio Superti-Furga and the RESOLUTE consortium team8 members describe the development of many resources available for research on SLC transporters. Included in the resources are databases and knowledgebases, videos, and open access plasmids and cell lines of SLC transporters. The public–private partnership includes six partners from academia and six from industry and has greatly enabled transporter research at the interface of drug-discovery.

In conclusion, this issue of CPT, which represents the third themed issue focused on transporters in the last decade, shows the incredible work and advancement the past 10 years have brought to the field and is the most-comprehensive look at transporters to date. It includes a greatly expanded breadth of research topics as our understanding of transporters has advanced from important proteins in pharmacokinetics to targets for common and rare diseases, drug toxicity targets, and important determinants of total body homeostasis. We hope you enjoy reading the entire issue and that you bookmark some of the articles as important references for the expanded understanding of transporters in clinical pharmacology.



中文翻译:

不仅仅是药代动力学:临床药理学中的转运蛋白

通过药代动力学和药效学机制,膜转运蛋白在治疗和药物不良反应中起着至关重要的作用(1)。2列出了控制不同器官吸收、分布和消除的关键转运蛋白。它们在影响内源性物质和药物处置方面的关键作用可以使用各种工具来描述(3)。

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图1
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临床药理学与治疗学2022 年 9 月封面图片:转运蛋白。
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图 2
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显示肠道肝脏和肾脏中重要的多特异性药物转运蛋白的图表。箭头表示主要的运输方向,尽管有些运输工具是双向的。所示的转运蛋白是临床上重要的药物-药物相互作用的主要靶标。4该图是使用 biorender.com 创建的。
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图 3
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临床药理学转运蛋白研究中使用的不同组学方法和技术。该图是使用 biorender.com 创建的,是从参考文献中提取的。本期《临床药理学与治疗学》第3期。

本期临床药理学与治疗学( CPT )主题期刊中包含由国际转运蛋白联盟 (ITC) 成员共同撰写的手稿,该联盟是一个由转运蛋白专家组成的多部门组织,十多年来一直是转运蛋白的思想领袖在药物发现和开发的界面,1来自 RESOLUTE 联盟的研究人员,2公私合作伙伴关系,其使命是扩大对溶质载体 (SLC) 的全球研究,以及来自世界各地工业和学术机构的广泛作者. 例如,Brouwer等人的手稿., “Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper for ITC,” 3描述了从基因调控和 microRNA 到翻译后修饰和贩运的关键机制和因素,药物转运蛋白在具有药理意义的组织中的表达和活性。已知通过核受体(例如孕烷 X 受体 (PXR) 介导的酶诱导)调节肝药物代谢酶在许多药物的药代动力学和药效学的个体间变化中起主要作用。正如 Brouwer等人强调的那样.,这些相同的核受体中的一些,例如 PXR 和法尼醇 X 激活受体 (FXR),参与了肝转运蛋白的调节,因此介导了参与异生物质消除的基因和蛋白质的高度协调水平的调节(即转运蛋白和酶)。Brouwer等人的表 2 和表 3 。介绍了肠道和肝脏中转运蛋白调节所涉及的主要机制,并为临床药理学家提供了关键参考材料,以寻求了解药物吸收和消除个体间差异所涉及的机制。该手稿最后呼吁进行更多研究,以弥合涉及药物吸收和消除的转运蛋白和酶调节的复杂机制中的知识空白。

另一份手稿“药物发现和开发中 SLC 和 ABC 转运蛋白的新兴研究:国际转运蛋白联盟的展望”,呼应了更多研究和应用新技术来缩小转运蛋白知识差距的呼吁。4在这份手稿中,作者描述了在过去十年中使膜转运蛋白研究取得巨大进展的大量新技术。作者强调了基础、转化和临床研究水平的进展。例如,低温电子显微镜的应用导致 ATP 结合盒 (ABC) 超家族和 SLC 超家族中许多膜转运蛋白的高分辨率结构过多。这些结构极大地提高了通过分子对接方法在药物发现工作中靶向转运蛋白的能力。在过去 5 年中进行的转化蛋白质组学研究导致了对各种组织中转运蛋白丰度的定量理解,这反过来又为基于生理的药代动力学模型 (PBPK) 提供了信息。描述了临床研究的进展,包括新的临床工具,例如组织衍生的小细胞外囊泡。这些囊泡包括源自特定组织的外泌体,表达转运蛋白和酶,可用作药代动力学和药效学的生物标志物。该手稿还描述了一组小分子,例如尿酸和胆红素,它们通常存在于个体患者的健康记录中,可用作转运蛋白活性和表达的真实世界生物标志物。例如,尿酸是 BCRP (ABCG2) 的生物标志物,而胆红素是 OATP1B1 (SLCO1B1) 的生物标志物。表达转运蛋白和酶,可用作药代动力学和药效学的生物标志物。该手稿还描述了一组小分子,例如尿酸和胆红素,它们通常存在于个体患者的健康记录中,可用作转运蛋白活性和表达的真实世界生物标志物。例如,尿酸是 BCRP (ABCG2) 的生物标志物,而胆红素是 OATP1B1 (SLCO1B1) 的生物标志物。表达转运蛋白和酶,可用作药代动力学和药效学的生物标志物。该手稿还描述了一组小分子,例如尿酸和胆红素,它们通常存在于个体患者的健康记录中,可用作转运蛋白活性和表达的真实世界生物标志物。例如,尿酸是 BCRP (ABCG2) 的生物标志物,而胆红素是 OATP1B1 (SLCO1B1) 的生物标志物。

在 2018 年 11 月号CPT发表的上一期转运蛋白主题中,生物标志物作为药物转运蛋白研究的一个新领域被引入。5到 2022 年,转运蛋白生物标志物现已常规用于药代动力学和药物-药物相互作用研究。在本期CPT中,有几篇原创研究文章专注于转运蛋白生物标志物。Takita等人,在“粪卟啉 I 作为内源性生物标志物检测 OATP1B 活性降低和慢性肾病消除途径转变”中,6使用血浆中的粪卟啉 I (CPI) 水平来了解慢性肾脏病 (CKD)、肝脏摄取药物和利福平抑制肝脏转运之间的复杂相互作用,这在 CKD 患者中比在健康志愿者中更为显着。这项优雅的研究将 PBPK 模型扩展到 CKD 患者,以检测作为肝脏转运蛋白 OATP1B1 底物的药物的 CKD 与药物相互作用风险,这些药物也部分被肾脏清除。作者得出结论,在 CKD 中,CPI 肾脏消除实际上消失了,导致 OATP1B1 转运的内源性分子比例增加。因此,与没有肾功能不全的患者相比,抑制 OATP1B1 对 CKD 患者 CPI 水平的影响更大。

另一篇关于生物标志物的有趣原创研究文章来自 Nigam 实验室,“用药物丙磺舒治疗后阻断人体有机阴离子转运会导致血浆和尿液中的重大代谢改变。” 7这份手稿探讨了肾脏有机阴离子转运蛋白抑制剂丙磺舒对 20 名健康志愿者血浆和尿液内源性代谢物水平的影响。通过测量血浆和尿液,研究人员可以识别肾分泌有机阴离子转运蛋白的内源性底物,专门寻找血浆中升高但尿液中减少的代谢物。有趣的是,他们发现了各种各样的分子(大约 100 种),包括一些已知的肠道微生物组产品。通过使用具有特定敲除有机阴离子转运蛋白 1 (OAT1, SLC22A6 ) 或有机阴离子转运蛋白 3 (OAT3, SLC22A8 ) 的小鼠),他们在健康志愿者中验证了丙磺舒研究中确定的代谢物子集,并检测了哪些代谢物对两种主要的有机阴离子转运体中的每一种都具有特异性。由于小鼠和人类转运蛋白之间的潜在物种差异以及内源性分子的不同代谢途径,因此需要小心解释数据。尽管如此,这项研究与遥感和信号理论一致,这表明 SLC22 家族中的混杂转运蛋白是人类新陈代谢的关键决定因素。

最后,该问题包括关于转运体研究的几个有趣的观点。值得注意的是,Giulio Superti-Furga 和 RESOLUTE 联盟团队8名成员描述了许多可用于 SLC 转运蛋白研究的资源的开发。资源中包括数据库和知识库、视频以及 SLC 转运蛋白的开放获取质粒和细胞系。公私合作伙伴关系包括六个来自学术界的合作伙伴和六个来自工业界的合作伙伴,极大地促进了药物发现界面的转运蛋白研究。

总而言之,本期CPT是过去十年来关注运输者的第三期主题,展示了过去 10 年为该领域带来的令人难以置信的工作和进步,是迄今为止对运输者最全面的看法。随着我们对转运蛋白的理解已经从药代动力学中的重要蛋白质发展到常见和罕见疾病的靶标、药物毒性靶标和全身稳态的重要决定因素,它包括了极大扩展的研究主题。我们希望您喜欢阅读整期文章,并希望您将其中的一些文章添加为重要参考,以扩大对临床药理学中转运蛋白的理解。

更新日期:2022-08-22
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