Shirasaka Yoshiyuki, Li Yan, Shibue Yuta, Kuraoka Erika, Spahn-Langguth Hildegard, Kato Yukio, Langguth Peter, Tamai Ikumi
Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
Pharm Res. 2009 Mar;26(3):560-7. doi: 10.1007/s11095-008-9771-4. Epub 2008 Nov 12.
The purpose of this study is to clarify the impact of P-gp and Oatp on intestinal absorption of the beta(1)-adrenoceptor antagonist talinolol.
P-gp-mediated transport was measured in LLC-PK1/MDR1 cells. Oatp-mediated uptake was evaluated with Xenopus oocytes expressing Oatp1a5. Rat intestinal permeability was measured by the in situ closed loop method. In vivo absorption was pharmacokinetically assessed by measuring plasma concentration after oral administration in rats.
In LLC-PK1/MDR1 cells, the permeability of talinolol was markedly higher in the secretory direction than in the absorptive one. The uptake of talinolol by Xenopus oocytes expressing Oatp1a5 was significantly increased compared with that by water-injected oocytes. Naringin inhibited talinolol uptake by Oatp1a5 (IC (50) = 12.7 microM). The reported IC (50) value of naringin for P-gp-mediated transport of talinolol is approximately 2,000 microM. Rat intestinal permeability of talinolol was significantly decreased in the presence of 200 microM naringin, but was significantly increased by 2,000 microM naringin. Similar results were obtained in in vivo absorption studies in rats.
The absorption behavior of talinolol can be explained by the involvement of both P-gp and Oatp, based on characterization of talinolol transport by Oatp1a5 and P-gp, and the effects of naringin.
本研究旨在阐明P-糖蛋白（P-gp）和有机阴离子转运多肽（Oatp）对β1肾上腺素能受体拮抗剂他林洛尔肠道吸收的影响。
在LLC-PK1/MDR1细胞中测定P-gp介导的转运。用表达Oatp1a5的非洲爪蟾卵母细胞评估Oatp介导的摄取。采用原位闭环法测定大鼠肠道通透性。通过测定大鼠口服给药后的血浆浓度，对体内吸收进行药代动力学评估。
在LLC-PK1/MDR1细胞中，他林洛尔的分泌方向通透性明显高于吸收方向。与注射水的卵母细胞相比，表达Oatp1a5的非洲爪蟾卵母细胞对他林洛尔的摄取显著增加。柚皮苷抑制Oatp1a5对他林洛尔的摄取（半数抑制浓度（IC50）=12.7微摩尔）。报道的柚皮苷对P-gp介导的他林洛尔转运的IC50值约为2000微摩尔。在存在200微摩尔柚皮苷的情况下，大鼠肠道对他林洛尔的通透性显著降低，但在2000微摩尔柚皮苷作用下显著增加。在大鼠体内吸收研究中也获得了类似结果。
基于Oatp1a5和P-gp对他林洛尔转运的特征以及柚皮苷的作用，他林洛尔的吸收行为可通过P-gp和Oatp的共同参与来解释。
