Hydrophilic anti-migraine triptans are substrates for OATP1A2, a transporter expressed at human blood-brain barrier

作者：Cheng, Ziqiang^*; Liu, Houfu; Yu, Na; Wang, Fei; An, Gang; Xu, Yan; Liu, Qian; Guan, Chen-bing; Ayrton, Andrew

来源：Xenobiotica, 2012, 42(9): 880-890.

DOI：10.3109/00498254.2012.675455

• OATP1A2
• triptans
• blood-brain barrier
• uptake transporter

1. OATP1A2 is expressed in the luminal membrane of human blood-brain barrier (BBB). The human tissue with the highest OATP1A2 mRNA expression is the brain. @@@ 2. We have established a robust BacMam2-OATP1A2 transduced HEK293 system. Among the 36 central nervous system (CNS) marketed drugs tested, hydrophilic triptans, 5-HT1B/1D receptor agonists for the treatment of migraine attacks, were identified as OATP1A2 substrates. Kinetics (K-m and V-max) were determined for six marketed triptans. @@@ 3. Structure-activity relationship (SAR) obtained from 18 triptan structural analogs revealed that the positively charged basic amine atom was essential for efficient OATP1A2-mediated triptan uptake and uptake rate was in the order of tertiary > secondary > primary. @@@ 4. Preliminary quantitative SAR analysis of the triptan analogs demonstrated positive correlation between OATP1A2-mediated uptake rate and van der Waals volume (vdw_vol). @@@ 5. OATP1A2 was specifically expressed on the apical side of MDCKII monolayer after BacMam2-OATP1A2 transduction and can facilitate transport of triptans across the MDCKII monolayer from apical to basolateral side. Involvement of OATP1A2 for brain penetration of triptans in human requires further investigation.

• 出版日期2012-9
• 单位上海交通大学