Solute Carrier Family of the Organic Anion-Transporting Polypeptides 1A2-Madin-Darby Canine Kidney II: A Promising In Vitro System to Understand the Role of Organic Anion-Transporting Polypeptide 1A2 in Blood-Brain Barrier Drug Penetration

被引:37
作者
Liu, Houfu [1 ]
Yu, Na [1 ]
Lu, Sijie [1 ]
Ito, Sumito [4 ]
Zhang, Xuan [4 ]
Prasad, Bhagwat [6 ]
He, Enuo [3 ]
Lu, Xinyan [1 ]
Li, Yang [1 ]
Wang, Fei [1 ]
Xu, Han [2 ]
An, Gang [2 ]
Unadkat, Jashvant D. [6 ]
Kusuhara, Hiroyuki [4 ]
Sugiyama, Yuichi [5 ]
Sahi, Jasminder [1 ]
机构
[1] GlaxoSmithKline Res & Dev Ltd, Drug Metab & Pharmacokinet, Shanghai, Peoples R China
[2] GlaxoSmithKline Res & Dev Ltd, Mol Discovery Res, Shanghai, Peoples R China
[3] GlaxoSmithKline, Modelling & Translat Biol Platform Technol & Sci, Ware, Herts, England
[4] Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Mol Pharmacokinet, Tokyo, Japan
[5] RIKEN, Res Cluster Innovat, RIKEN Innovat Ctr, Sugiyama Lab, Yokohama, Kanagawa, Japan
[6] Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA
关键词
D O I
10.1124/dmd.115.064170
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Organic anion-transporting polypeptide (OATP) 1A2 has the potential to be a target for central nervous system drug delivery due to its luminal localization at the human blood-brain barrier and broad substrate specificity. We found OATP1A2 mRNA expression in the human brain to be comparable to breast cancer resistance protein and OATP2B1 and much higher than P-glycoprotein (P-gp), and confirmed greater expression in the brain relative to other tissues. The goal of this study was to establish a model system to explore OATP1A2-mediated transcellular transport of substrate drugs and the interplay with P-gp. In vitro (human embryonic kidney 293 cells stably expressing Oatp1a4, the closest murine isoform) and in vivo (naive and Oatp1a4 knock-out mice) studies with OATP1A2 substrate triptan drugs demonstrated that these drugs were not Oatp1a4 substrates. This species difference demonstrates that the rodent is not a good model to investigate the active brain uptake of potential OATP1A2 substrates. Thus, we constructed a novel OATP1A2 expressing Madin-Darby canine kidney (MDCK) II wild type and an MDCKII-multidrug resistance protein 1 (MDR1) system using BacMam virus transduction. The spatial expression pattern of OATP1A2 after transduction in MDCKII-MDR1 cells was superimposed to P-gp, confirming apical membrane localization. OATP1A2-mediated uptake of zolmitriptan, rosuvastatin, and fexofenadine across monolayers increased with increasing OATP1A2 protein expression. OATP1A2 counteracted P-gp efflux for cosubstrates zolmitriptan and fexofenadine. A three-compartment model incorporating OATP1A2-mediated influx was used to quantitatively describe the time-and concentration-dependent apical-to-basolateral transcellular transport of rosuvastatin across OATP1A2 expressing the MDCKII monolayer. This novel, simple and versatile experimental system is useful for understanding the contribution of OATP1A2-mediated transcellular transport across barriers, such as the blood-brain barrier.
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收藏
页码:1008 / 1018
页数:11
相关论文
共 48 条
[1]   Interaction of methotrexate with organic-anion transporting polypeptide 1A2 and its genetic variants [J].
Badagnani, Ilaria ;
Castro, Richard A. ;
Taylor, Travis R. ;
Brett, Claire M. ;
Huang, Conrad C. ;
Stryke, Douglas ;
Kawamoto, Michiko ;
Johns, Susan J. ;
Ferrin, Thomas E. ;
Carlson, Elaine J. ;
Burchard, Esteban G. ;
Giacomini, Kathleen M. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2006, 318 (02) :521-529
[2]   Blood-brain barrier penetration of zolmitriptan -: Modelling of positron emission tomography data [J].
Bergström, M ;
Yates, R ;
Wall, A ;
Kågedal, M ;
Syvänen, S ;
Långström, B .
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, 2006, 33 (01) :75-91
[3]   Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: A resource for investigations into drug disposition [J].
Bleasby, K. ;
Castle, J. C. ;
Roberts, C. J. ;
Cheng, C. ;
Bailey, W. J. ;
Sina, J. F. ;
Kulkarni, A. V. ;
Hafey, M. J. ;
Evers, R. ;
Johnson, J. M. ;
Ulrich, R. G. ;
Slatter, J. G. .
XENOBIOTICA, 2006, 36 (10-11) :963-988
[4]   Evidence for an active transport of morphine-6-β-D-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier [J].
Bourasset, F ;
Cisternino, S ;
Temsamani, J ;
Scherrmann, JM .
JOURNAL OF NEUROCHEMISTRY, 2003, 86 (06) :1564-1567
[5]   ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier [J].
Bronger, H ;
König, J ;
Kopplow, K ;
Steiner, HH ;
Ahmadi, R ;
Herold-Mende, C ;
Keppler, D ;
Nies, AT .
CANCER RESEARCH, 2005, 65 (24) :11419-11428
[6]   Tissue distribution and ontogeny of mouse organic anion transporting polypeptides (Oatps) [J].
Cheng, XG ;
Maher, J ;
Chen, C ;
Klaassen, CD .
DRUG METABOLISM AND DISPOSITION, 2005, 33 (07) :1062-1073
[7]   Hydrophilic anti-migraine triptans are substrates for OATP1A2, a transporter expressed at human blood-brain barrier [J].
Cheng, Ziqiang ;
Liu, Houfu ;
Yu, Na ;
Wang, Fei ;
An, Gang ;
Xu, Yan ;
Liu, Qian ;
Guan, Chen-bing ;
Ayrton, Andrew .
XENOBIOTICA, 2012, 42 (09) :880-890
[8]   Role of statins in the treatment of multiple sclerosis [J].
Ciurleo, Rosella ;
Bramanti, Placido ;
Marino, Silvia .
PHARMACOLOGICAL RESEARCH, 2014, 87 :133-143
[9]  
Cvetkovic M, 1999, DRUG METAB DISPOS, V27, P866
[10]  
DIXON CM, 1993, DRUG METAB DISPOS, V21, P761