TY - JOUR T1 - SLCO1A2-MDCKII: a Promising in vitro System to Understand the Role of OATP1A2 in Blood Brain Barrier Drug Penetration JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.115.064170 SP - dmd.115.064170 AU - Houfu Liu AU - Na Yu AU - Sijie Lu AU - Sumito Ito AU - Xuan Zhang AU - Bhagwat Prasad AU - Enuo He AU - Xinyan Lu AU - Yang Li AU - Fei Wang AU - Han Xu AU - Gang An AU - Jashvant D. Unadkat AU - Hiroyuki Kusuhara AU - Yuichi Sugiyama AU - Jasminder Sahi Y1 - 2015/04/23 UR - http://dmd.aspetjournals.org/content/early/2015/04/23/dmd.115.064170.abstract N2 - OATP1A2 has the potential to be a target for CNS drug delivery due to its luminal localization at the human blood-brain barrier and broad substrate specificity. We confirmed greater OATP1A2 mRNA expression in human brain relative to other tissues and report OATP1A2 expression comparable to BCRP and OATP2B1 and much higher than P-gp. Our goal was to establish a model system to explore OATP1A2-mediated transcellular transport of substrate drugs and use this understand the interplay of this uptake transporter with the efflux pump, P-gp. In vitro (HEK293 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 were not Oatp1a4 substrates. This species difference indicated that the rodent is not the right model to investigate active brain uptake of potential OATP1A2 substrates. We then constructed a novel OATP1A2 expressing MDCKII-wild type (WT) and MDCKII-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 co-substrates zolmitriptan and fexofenadine. A three-compartment model incorporating OATP1A2-mediated influx was used successfully to quantitatively describe the time- and concentration-dependent apical-to-basolateral transcellular transport of rosuvastatin across OATP1A2 expressing MDCKII monolayers. 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. ER -