中国新药杂志

肺细胞药物转运体研究进展

PDF下载

张小莉 ¹^,² , 毛鑫羽 ¹^,² , 李自强 ¹ , 黄宇虹 ¹ , 王保和 ¹

中国新药杂志 | 综述 2021,30(8): 705-711

收起

中国新药杂志 |综述 2021 , 30 (8) : 705 -711

肺细胞药物转运体研究进展

全屏

张小莉¹^,², 毛鑫羽¹^,², 李自强¹, 黄宇虹¹, 王保和¹

作者信息

¹天津中医药大学第二附属医院，天津　300250

²天津中医药大学，天津　301617

通讯作者:

李自强，男，副研究员，主要从事药动学研究。E-mail：lzqpharm@126.com。

黄宇虹，女，教授，主要从事临床药理研究。E-mail：hyh101@126.com。

作者简介:

张小莉，女，硕士研究生，主要从事中药新药研发与临床评价。E-mail：1325162874@qq.com。

Progress in researches on drug transporters in lung

Xiao-li ZHANG¹^,², Xin-yu MAO¹^,², Zi-qiang LI¹, Yu-hong HUANG¹, Bao-he WANG¹

Affiliations

¹Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300250, China

²Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China

出版时间: 2021-04-30

文章导航

摘要

收起

肺脏是机体重要的呼吸器官，参与药物的体内循环、局部吸收及代谢。吸入型药物具有吸收快、起效快及避免首过代谢的特点，近年来备受关注。肺上皮细胞转运体在药物的摄取和外排中起重要作用，影响肺中的药物浓度及其在局部、全身药动学和疗效。肺脏药物转运体对药物的组织分布和药物相互作用有重要的影响。本文从肺细胞药物转运体的分布特征、表达水平、研究方法及临床意义等方面进行系统综述，以期为疾病治疗及新药开发提供参考。

关键词

肺细胞 / 药物转运体 / 吸入型药物 / 药物相互作用 / 组织分布

Abstract

收起

Lung, a vital respiratory organ of the body, participates in the internal circulation, local absorption and metabolism of drugs. Inhaled drugs have the characteristics of fast absorption, quick onset and avoiding first pass metabolism, which have attracted much attention in recent years. Pulmonary epithelial cell transporters play an important role in drug uptake and efflux, affecting drug concentration, local and systemic pharmacokinetics and efficacy. Lung drug transporters play an important role in drug distribution and drug interactions. This article systematically reviews the distribution characteristics, expression level, research methods and clinical significance of lung drug transporters in order to provide guidance for disease treatment and new drug development.

Key words

lung cells / drug transporters / inhaled drugs / drug interactions / tissue distribution

引用本文

张小莉, 毛鑫羽, 李自强, 黄宇虹, 王保和. 肺细胞药物转运体研究进展. 中国新药杂志, 2021 , 30 (8) : 705 -711 .

Xiao-li ZHANG, Xin-yu MAO, Zi-qiang LI, Yu-hong HUANG, Bao-he WANG. Progress in researches on drug transporters in lung[J]. Chinese Journal of New Drugs, 2021 , 30 (8) : 705 -711 .

基金

收起

天津市自然科学基金项目(18JCQNJC83800)
天津市科技计划项目(17ZXXYSY00060)
国家“重大新药创制”科技重大专项资助项目(2018ZX09734-002)

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

[1]

U. S. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). In Vitro Drug Interaction Studies—Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry[EB/OL]. [2020-01-23]. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

[2]

U. S. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Clinical Drug Interaction Studies—Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry[EB/OL]. [2020-01-23]. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

[3]

BERG T, HEGELUND MYRBÄCK T, OLSSON M, et al. Gene expression analysis of membrane transporters and drug-metabolizing enzymes in the lung of healthy and COPD subjects[J]. Pharmacol Res Perspect, 2014, 2(4): e00054.

[4]

FALLON JK, HOUVIG N, BOOTH-GENTHE CL, et al. Quantification of membrane transporter proteins in human lung and immortalized cell lines using targeted quantitative proteomic analysis by isotope dilution nanoLC-MS/MS[J]. J Pharm Biomed Anal, 2018, 154: 150-157.

[5]

SAKAMOTO A, MATSUMARU T, YAMAMURA N, et al. Quantitative expression of human drug transporter proteins in lung tissues: analysis of regional, gender, and interindividual differences by liquid chromatography-tandem mass spectrometry[J]. J Pharm Sci, 2013, 102(9): 3395-3406.

[6]

VESEL M, RAPP J, FELLER D, et al. ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling[J]. Respir Res, 2017, 18(1): 52.

[7]

BERG T, HEGELUND-MYRBÄCK T, ÖCKINGER J, et al. Expression of MATE1, P-gp, OCTN1 and OCTN2, in epithelial and immune cells in the lung of COPD and healthy individuals[J]. Respir Res, 2018, 19(1): 68.

[8]

SAKAMOTO A, MATSUMARU T, YAMAMURA N, et al. Drug transporter protein quantification of immortalized human lung cell lines derived from tracheobronchial epithelial cells (calu-3 and BEAS2-B), bronchiolar-alveolar cells (NCI-H292 and NCI-H441), and alveolar type II-like cells (A549) by liquid chromatography-tandem mass spectrometry[J]. J Pharm Sci, 2015, 104(9): 3029-3038.

[9]

SALOMON JJ, MUCHITSCH VE, GAUSTERER JC, et al. The cell line NCl-H441 is a useful in vitro model for transport studies of human distal lung epithelial barrier[J]. Mol Pharm, 2014, 11(3): 995-1006.

[10]

AGUIAR JA, TAMMINGA A, LOBB B, et al. The impact of cigarette smoke exposure, COPD, or asthma status on ABC transporter gene expression in human airway epithelial cells[J]. Sci Rep, 2019, 9(1): 153.

[11]

ZUKAUSKAS A, MRSNY RJ, CORTÉS BARRANTES P, et al. Transporters MRP1 and MRP2 regulate opposing inflammatory signals to control transepithelial neutrophil migration during Streptococcus pneumoniae lung infection[J]. mSphere, 2018, 3(4): e00303-e00318.

[12]

黄燕玲, 罗光伟, 毛莉娜. 慢性阻塞性肺病大鼠血浆白三烯C4水平、细胞免疫及支气管上皮多药耐药相关蛋白1 mRNA和蛋白水平的变化[J]. 中国老年学杂志, 2018, 38(4): 923-925.

[13]

WANG H, CHI CH, ZHANG Y, et al. Effects of histone deacetylase inhibitors on ATP-binding cassette transporters in lung cancer A549 and colorectal cancer HCT116 cells[J]. Oncol Lett, 2019, 18(1): 63-71.

[14]

PATURI DK, KWATRA D, ANANTHULA HK, et al. Identification and functional characterization of breast cancer resistance protein in human bronchial epithelial cells (Calu-3)[J]. Int J Pharm, 2010, 384(1-2): 32-38.

[15]

QIU ZQ, ZHAO K. Expression of ERCC1, RRM1 and LRP in non-small cell lung cancers and their influence on chemotherapeutic efficacy of gemcitabine concomitant with nedaplatin[J]. Asian Pac J Cancer Prev, 2014, 15(17): 7303-7307.

[16]

李杰, 龚民, 崔永, 等. 肺耐药蛋白LRP在肺癌中的表达及意义[J]. 现代肿瘤医学, 2014, 22(12): 2875-2879.

[17]

白璐, 李莉红. RP、P-gp、GST-π蛋白在非小细胞肺癌中的表达及其临床意义[J]. 实用癌症杂志, 2017, 32(2): 204-206.

[18]

HUANG W, MAO Y, ZHAN Y, et al. Prognostic implications of survivin and lung resistance protein in advanced non-small cell lung cancer treated with platinum-based chemotherapy[J]. Oncol Lett, 2016, 11(1): 723-730.

[19]

SONETT J, GOLDKLANG M, SKLEPKIEWICZ P, et al. A critical role for ABC transporters in persistent lung inflammation in the development of emphysema after smoke exposure[J]. Faseb J, 2018: fj201701381.

[20]

NAKANISHI T, HASEGAWA Y, HARUTA T, et al. In vivo evidence of organic cation transporter-mediated tracheal accumulation of the anticholinergic agent ipratropium in mice[J]. J Pharm Sci, 2013, 102(9): 3373-3381.

[21]

SALOMON JJ, ENDTER S, TACHON G, et al. Transport of the fluorescent organic cation 4-(4-(dimethylamino) styryl)-N-methylpyridinium iodide (ASP+) in human respiratory epithelial cells[J]. Eur J Pharm Biopharm, 2012, 81(2): 351-359.

[22]

NAKAMURA T, NAKANISHI T, HARUTA T, et al. Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic cation/carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated pulmonary absorption[J]. Mol Pharm, 2010, 7(1): 187-195.

[23]

COURCOT E, LECLERC J, LAFITTE JJ, et al. Xenobiotic metabolism and disposition in human lung cell models: comparison with in vivo expression profiles[J]. Drug Metab Dispos, 2012, 40(10): 1953-1965.

[24]

MUKHERJEE M, PRITCHARD DI, BOSQUILLON C. Evaluation of air-interfaced Calu-3 cell layers for investigation of inhaled drug interactions with organic cation transporters in vitro[J]. Int J Pharm, 2012, 426(1-2): 7-14.

[25]

INGOGLIA F, VISIGALLI R, ROTOLI BM, et al. Functional characterization of the organic cation transporters (OCTs) in human airway pulmonary epithelial cells[J]. Biochim Biophys Acta, 2015, 1848(7): 1563-1572.

[26]

TAKANO M, SUGIMOTO N, EHRHARDT C, et al. Functional expression of PEPT2 in the human distal lung epithelial cell line NCl-H441[J]. Pharm Res, 2015, 32(12): 3916-3926.

[27]

NAKANISHI T, HASEGAWA Y, MIMURA R, et al. Prostaglandin transporter (PGT/SLCO2A1) protects the lung from bleomycin-induced fibrosis[J]. PLoS One, 2015, 10(4): e0123895.

[28]

CHANG HY, LOCKER J, LU R, et al. Failure of postnatal ductus arteriosus closure in prostaglandin transporter-deficient mice[J]. Circulation, 2010, 121(4): 529-536.

[29]

SHIRASAKA Y, SHICHIRI M, KASAI, et al. A role of prostaglandin transporter in regulating PGE₂ release from human bronchial epithelial BEAS-2B cells in response to LPS[J]. J Endocrinol, 2013, 217(3): 265-274.

[30]

SAKAMOTO A, SUZUKI S, MATSUMARU T, et al. Correlation of organic cation/carnitine transporter 1 and multidrug resistance-associated protein 1 transport activities with protein expression levels in primary cultured human tracheal, bronchial, and alveolar epithelial cells[J]. J Pharm Sci, 2016, 105(2): 876-883.

[31]

GOSE T, NAKANISHI T, KAMO S, et al. Prostaglandin transporter (OATP2A1/SLCO2A1) contributes to local disposition of eicosapentaenoic acid-derived PGE3[J]. Prostaglandins Other Lipid Mediat, 2016, 122: 10-17.

[32]

SALOMON JJ, HAGOS Y, PETZKE S, et al. Beta-2 adrenergic agonists are substrates and inhibitors of human organic cation transporter 1[J]. Mol Pharm, 2015, 12(8): 2633-2641.

[33]

CAZZOLA M, CALZETTA L, PAGE CP, et al. Use of indacaterol for the treatment of COPD: a pharmacokinetic evaluation[J]. Expert Opin Drug Metab Toxicol, 2014, 10(1): 129-137.

[34]

ITO N, ITO K, IKEBUCHI Y, et al. Organic cation transporter/solute carrier family 22a is involved in drug transfer into milk in mice[J]. J Pharm Sci, 2014, 103(10): 3342-3348.

[35]

CADA DJ, INGRAM K, LEONARD J, et al. Umeclidinium bromide and vilanterol trifenatate inhalation powder[J]. Hosp Pharm, 2014, 49(6): 554-562.

[36]

ONG HX, TRAINI D, BEBAWY M, et al. Ciprofloxacin is actively transported across bronchial lung epithelial cells using a Calu-3 air interface cell model[J]. Antimicrob Agents Chemother, 2013, 57(6): 2535-2540.

[37]

HAGOS FT, DAOOD MJ, OCQUE JA, et al. Probenecid, an organic anion transporter 1 and 3 inhibitor, increases plasma and brain exposure of N-acetylcysteine[J]. Xenobiotica, 2017, 47(4): 346-353.

[38]

HORVATH G, MENDES ES, SCHMID N, et al. The effect of corticosteroids on the disposal of long-acting beta2-agonists by airway smooth muscle cells[J]. J Allergy Clin Immunol, 2007, 120(5): 1103-1109.

[39]

ZHANG ZX, YE S, ZHANG M, et al. High expression of SLC34A2 is a favorable prognostic marker in lung adenocarcinoma patients[J]. Tumour Biol, 2017, 39(7): 1010428317720212.

[40]

SALOMON JJ, GAUSTERER JC, SELO MA, et al. OCTN2-mediated acetyl-l-carnitine transport in human pulmonary epithelial cells in vitro[J]. Pharmaceutics, 2019, 11(8): 396.

2021年第30卷第8期

PDF下载

引用本文

BibTeX

文章信息

首发时间：2026-10-28
出版时间：2021-04-30

补充材料

相关文章

文章信息

作者

出版历史

录用日期：2020-09-21

基金

天津市自然科学基金项目(18JCQNJC83800)

天津市科技计划项目(17ZXXYSY00060)

国家“重大新药创制”科技重大专项资助项目(2018ZX09734-002)

作者信息

¹天津中医药大学第二附属医院，天津　300250

²天津中医药大学，天津　301617

通讯作者:

李自强，男，副研究员，主要从事药动学研究。E-mail：lzqpharm@126.com。

黄宇虹，女，教授，主要从事临床药理研究。E-mail：hyh101@126.com。

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/zgxyzz/CN/1322245675618784084

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT