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transporters(OATs and OATPs) contribute to illustrate the mechanism of medicinal compatibility of ingredients with different properties in yuanhuzhitong prescription

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Acta Pharmaceutica Sinica B 2020年第9期10卷 1646-1657页

作者： Ze Wang Haihua Shang Yazhuo Li Chen Zhang Yan Dong Tao Cui Hongbing Zhang Xiaoyan Ci Xiulin Yi Tiejun Zhang Fengying Yan Yaping Zhang Xing Huang Weidang Wu Changxiao Liu Tianjin University of Traditional Chinese Medicine Tianjin 300193China Biotechnology Center Tianjin Institute of Pharmaceutical Research Co.Ltd.Tianjin 300193China Tianjin Institute of Pharmaceutical Research New Drug Evaluation Research Co.Ltd. State Key Laboratory of Drug Release Technology and PharmacokineticsTianjin 300031China Chu Hsien-I Memorial Hospital Tianjin Medical UniversityTianjin 300134China Shenyang Pharmaceutical University Shenyang 110016China Anhui Medical University Hefei 230032China Emergency Department Zhongshan HospitalFudan UniversityShanghai 200032China Hefei Tianhui Hatching Technology Co.Ltd. Hefei 230032China

Various medicinal ingredients with different tastes are combined according to the theory of compatibility in Chinese materia medica to achieve a better efficacy,while the mechanism was not very ***,the authors studied the interaction between ingredients and human transporters such as the kidney transporters OAT1 and OAT3,the liver transporters OATP1 B1 and OATP1 B3,and the intestine transporter OATP2 B1 to discern the compatibility mechanism of ingredients with different tastes in the Yuanhuzhitong preparation(YHP)comprising Corydalis yanhusuo(CYH)and Angelica dahurica(AD),which could relieve pain by restraining the central *** results show that tetrahydropalmatine(TDE),the major component of CYH,could be transported by OAT3 into kidney,OATP1 B1 and OATP1 B3 into liver,while imperatorin(IPT)and isoimperatorin(ISP),the two key components of AD,and AD extract showed strong inhibition to OAT1 and ***’s more,AD extract also exerted strongly inhibition to human transporters OATP1 B1 and OATP1 *** was also detected that IPT,ISP,and AD extract significantly downregulated the expression of Oatplal,Oafp1 a4,and Oatp1 b2 of liver in *** in vivo results show that the concentration of TDE in liver and kidney significantly decreased,while the TDE concentration in blood and brain were both significantly enhanced in the presence of IPT,ISP,and AD *** results suggest that the ingredients in AD with pungent taste could enhance the exposure of TDE in blood and brain by inhibiting the uptake of TDE in liver and *** is to say,TDE with bitter taste could"flood up"into the central nervous system to play its therapeutic effect by the cut-off of that into liver and kidney in the presence of ingredients within *** paper not only proves the meridian distribution of CYH in liver and kidney with the role of OAT3,OATP1 B1,and OATP1 B3,but also illustrates how to improve the efficacy of CYH by reasonable compatibility with *** study may offer

关键词： transporters Drug-drug interaction Yuanhuzhitong prescription OAT1 OAT3 OATP1B1 OATP1B3 OATP2B1

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Renal drug transporters and their significance in drug–drug interactions

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Acta Pharmaceutica Sinica B 2016年第5期6卷 363-373,518页

作者： Jia Yin Joanne Wang Department of Pharmaceutics University of Washington

The kidney is a vital organ for the elimination of therapeutic drugs and their *** drug transporters,which are primarily located in the renal proximal tubules,play an important role in tubular secretion and reabsorption of drug molecules in the *** secretion is characterized by high clearance capacities,broad substrate specificities,and distinct charge selectivity for organic cations and *** the past two decades,substantial progress has been made in understanding the roles of transporters in drug disposition,efficacy,toxicity and drug–drug interactions(DDIs).In the kidney,several transporters are involved in renal handling of organic cation(OC) and organic anion(OA) *** transporters are increasingly recognized as the target for clinically significant *** review focuses on the functional characteristics of major human renal drug transporters and their involvement in clinically significant DDIs.

关键词： Renal drug transporters Drug–drug interactions Organic cations Organic anions Nephrotoxicity

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More transporters,More Substrates:The Arabidopsis Major Facilitator Superfamily Revisited

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Molecular Plant 2019年第9期12卷 1182-1202页

作者： Maria Nino-Gonzalez Esther Novo-Uzal Dale N.Richardson Pedro M.Barros Paula Duque Instituto Gulbenkian de Ciencia 2780-156 OeirasPortugal Genomics of Plant Stress Unit ITQB NOVA-Instituto de Tecnologia Quimica e Biologica Antonio XavierUniversidade Nova de Lisboa2780-157 OeirasPortugal

The Major Facilitator Superfamily(MFS)is ubiquitous in living organisms and represents the largest group of secondary active membrane *** plants,significant research efforts have focused on the role of specific families within the MFS,particularly those transporting macronutrients(C,N,and P)that constitute the vast majority of the members of this *** MFS families remain less explored,although a plethora of additional substrates and physiological functions have been ***,the lack of a systematic approach to analyzing the MFS as a whole has obscured the high diversity and versatility of these ***,we present a phylogenetic analysis of all annotated MFS domaincontaining proteins encoded in the Arab/dops/s fA?a//ana genome and propose that this superfamily of transporters consists of 218 members,clustered in 22 *** reviewing the available information regarding the diversity in biological functions and substrates of Arab/dops/s MFS members,we provide arguments for intensified research on these membrane transporters to unveil the breadth of their physiological relevance,disclose the molecular mechanisms underlying their mode of action,and explore their biotechnological potential.

关键词： Arabidopsis thaliana membrane transport MFS transporters phylogenetic analysis

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Characterizing drug-metabolizing enzymes and transporters that are bona fide CAR-target genes in mouse intestine

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Acta Pharmaceutica Sinica B 2016年第5期6卷 475-491页

作者： Shinhee Park Sunny Lihua Cheng Julia Yue Cui Department of Environmental and Occupational Health Sciences University of Washington

Intestine is responsible for the biotransformation of many orally-exposed *** constitutive androstane receptor(CAR/Nr1i3) is known to up-regulate many genes encoding drugmetabolizing enzymes and transporters(drug-processing genes/DPGs) in liver,but less is known regarding its effect in ***-day-old wild-type and Car / mice were administered the CARligand TCPOBOP or vehicle once daily for 4 *** wild-type mice,Car m RNA was down-regulated by TCPOBOP in liver and *** / mice had altered basal intestinal expression of many DPGs in a section-specific *** with the liver data(Aleksunes and Klaassen,2012),TCPOBOP upregulated many DPGs(Cyp2b10,Cyp3a11,Aldh1a1,Aldh1a7,Gsta1,Gsta4,Gstm1-m4,Gstt1,Ugt1a1,Ugt2b34,Ugt2b36,and Mrp2–4) in specific sections of small intestine in a CAR-dependent ***,the m RNAs of Nqo1 and Papss2 were previously known to be up-regulated by TCPOBOP in liver but were not altered in ***,many known CAR-target genes were highest expressed in colon where CAR is minimally expressed,suggesting that additional regulators are involved in regulating their *** conclusion,CAR regulates the basal expression of many DPGs in intestine,and although many hepatic CAR-targeted DPGs were bona fide CAR-targets in intestine,pharmacological activation of CAR in liver and intestine are not identical.

关键词： Drug-processing genes Intestine Mice CAR Drug-metabolizing enzymes transporters

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Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology

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World Journal of Gastroenterology 2015年第41期21卷 11862-11876页

作者： Vibeke Andersen Katrine Svenningsen Lina Almind Knudsen Axel Kornerup Hansen Uffe Holmskov Allan Stensballe Ulla Vogel Molecular Diagnostic and Clinical Health Research Unit Hospital of Southern Jutland Institute of Regional Health Research-Centre S?nderjylland University of Southern Denmark Medical Department Regional Hospital Viborg Experimental Animal Models University of Copenhagen Department of Cancer and Inflammation Research University of Southern Denmark Department of Health Science and Technology Aalborg University National Research Centre for the Working Environment

AIM: To evaluate ATP-binding cassette(ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer(CRC) development. METHODS: Literature search was conducted on Pub Med using combinations of the following terms: ABC transporters, ATP binding cassette transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein(P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2(MRP2) and ABCG2/breast cancer resistance protein(BCRP), Abcb1/Mdr1 a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function. RESULTS: Recently, human studies reported thatchanges in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes in relation to colitis was suggested by the animal studies. The finding that colitis was preceded by altered gut bacterial composition suggests that deletion of Abcb1 leads to fundamental changes of hostmicrobiota interaction. Also, high fat diet increases the frequency and severity of colitis in specific pathogenfree Abcb1 KO mice. The Abcb1 KO mice might thus serve as a model in which diet/environmental factors and microbes may be controlled and investigated in relation to intestinal inflammation. Potential molecular mechanisms include defective transport of inflammatory mediators and/or phospholipid translocation from one side to the other of the cell membrane lipid bilayer by ABC transporters affecting inflammatory response and/or function of tight junctions, phagocytosis and vesicle trafficking. Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters and which may additionally affect ABC transporter function through nuclear receptors and transcriptional regulation. Another critical role of ABCB1 was suggested by the finding that ABCB1 expr

关键词： ATP-binding cassette transporters Colorectal cance

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Organic anion transporters also mediate the drug–drug interaction between imipenem and cilastatin

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Asian Journal of Pharmaceutical Sciences 2020年第2期15卷 252-263页

作者： Yanna Zhu Xiaokui Huo Changyuan Wang Qiang Meng Zhihao Liu Huijun Sun Aiping Tan Xiaodong Ma Jinyong Peng Kexin Liu Department of Clinical Pharmacology College of PharmacyDalian Medical UniversityDalian 116044China College(Institute)of Integrative Medicine Dalian Medical UniversityDalian 116044China Provincial Key Laboratory for Pharmacokinetics and Transport Dalian Medical UniversityDalian 116044China Department of Pharmacy First Affiliated Hospital of Dalian Medical UniversityDalian 116011China

This study aimed to clarify that organic anion transporters(OATs)mediate the drug–drug interaction(DDI)between imipenem and *** co-administration with imipenem,the plasma concentrations and the plasma concentration-time curve(AUC)of cilastatin were significantly increased,while renal clearance and cumulative urinary excretion of cilastatin were *** the same time,imipenem significantly inhibited the uptake of cilastatin in rat kidney slices and in human OAT1(hOAT1)-HEK293 and human OAT3(hOAT3)-HEK293 ***,p-aminohippurate,and benzylpenicillin inhibited the uptake of imipenem and cilastatin in rat kidney slices and in hOAT1-and hOAT3-HEK 293 cells,*** uptakes of imipenem and cilastatin in hOAT1-and hOAT3-HEK 293 cells were significantly higher than that in mock-HEK-293 ***,the K m values of cilastatin were increased in the presence of imipenem with unchanged V max,indicating that imipenem inhibited the uptake of cilastatin in a competitive *** imipenem and cilastatin were co-administered,the level of imipenem was higher compared with imipenem alone both in vivo and in ***,cilastatin significantly inhibited the uptake of imipenem when dehydropeptidase-1(DPEP1)was silenced by RNAi technology in hOAT1-and hOAT3-HEK 293 *** conclusion,imipenem and cilastatin are the substrates of OAT1 and ***1 and OAT3 mediate the DDI between imipenem and ***,cilastatin also reduces the hydrolysis of imipenem by inhibiting the uptake of imipenem mediated by OAT1 and OAT3 in the kidney as a complement.

关键词： Imipenem/cilastatin Renal dipeptidase Organic anion transporters Drug-drug interaction

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ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: what is the way forward?

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World Journal of Gastroenterology 2018年第29期24卷 3222-3238页

作者： Aleksandra Adamska Marco Falasca Metabolic Signalling Group School of Pharmacy and Biomedical Sciences Curtin Health Innovation Research Institute Curtin University

Pancreatic ductal adenocarcinoma(PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATPbinding cassette(ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance(MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.

关键词： Pancreatic ductal adenocarcinoma Multidrug resistance ATP-binding cassette transporters Targeted therapies Pancreatic ductal adenocarcinoma prognosis Predictive markers

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Glutamine transporters as pharmacological targets: From function to drug design

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Asian Journal of Pharmaceutical Sciences 2020年第2期15卷 207-219页

作者： Mariafrancesca Scalise Lorena Pochini Michele Galluccio Lara Console Cesare Indiveri Department of DiBEST(Biologia Ecologia e Scienze della Terra)University of CalabriaArcavacata di Rende(CS)87036Italy

Among the different targets of administered drugs,there are membrane transporters that play also a role in drug delivery and ***,drug-transporter interactions are responsible for off-target effects of drugs underlying their *** improvement of the drug design process is subjected to the identification of those membrane transporters mostly relevant for drug absorption,delivery and side effect production.A peculiar group of proteins with great relevance to pharmacology is constituted by the membrane transporters responsible for managing glutamine traffic in different body *** interest around glutamine metabolism lies in its physio-pathological role;glutamine is considered a conditionally essential amino acid because highly proliferative cells have an increased request of glutamine that cannot be satisfied only by endogenous ***,glutamine transporters provide cells with this special *** the glutamine transporters,SLC1A5,SLC6A14,SLC6A19,SLC7A5,SLC7A8 and some members of SLC38 family are the best characterized,so far,in both physiological and pathological *** 3D structures have been solved by CryoEM;other structural data on these transporters have been obtained by computational *** with drugs have been described for several transporters of this *** some of them,the studies are at an advanced stage,for others,the studies are still in nuce and novel biochemical findings open intriguing perspectives.

关键词： Glutamine transporters Drug delivery Pharmacokinetics Screening Proteoliposome

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Emerging Jasmonate transporters

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Molecular Plant 2017年第5期10卷 659-661页

作者： Chi Tam Nguyen Enrico Martinoia Edward E. Farmer Department of Plant and Microbial Biology University of Zurich Zollikerstrasse 107 8008 Zurich Switzerland

Jasmonic acid （JA） and methyl jasmonate （MeJA） are highly mobile and, when applied to intact plants,, these compounds powerfully modulate gene expression. Moreover, activation of jasmonate-responsive genes usually occurs in tissues distal to the treatments. It therefore comes as no surprise that there are jasmonate transporters; these proteins are only now emerging and their discovery is important for a number of reasons. Firstlv.

关键词： Emerging Jasmonate transporters

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transporters Contributing to Iron Trafficking in Plants

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Molecular Plant 2011年第3期4卷 464-476页

作者： Sarah S. Conte Elsbeth L. Walker University of Massachusetts Amherst Biology Department 611 No. Pleasant St Amherst MA 01002 USA

This review will discuss recent progress in understanding the many roles of transporters in the whole-plant physiological processes that maintain iron （Fe） homeostasis. These processes include uptake from the soil via roots, control of transport from roots to above-ground parts of the plant, unloading of Fe from the xylem in above-ground parts, loading of Fe into mitochondria and plastids, transport of Fe to reproductive parts of the plant, and Fe mobilization during seed germination. In addition, we will discuss the mechanisms that plants use to cope with an apparently unintended conse- quence of Fe acquisition： the uptake of toxic heavy metals via Fe transporters. Rapid progress has been made in under- standing the transport processes involved in each of these areas in the last 5 years and this review will focus on this recent progress. We will also highlight the key questions regarding transport steps that remain to be elucidated.

关键词： Nutrient and metal transport transporters gene regulation iron nicotianamine phytosiderophores.

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