Renal tubular secretion of varenicline by multidrug and toxin extrusion (MATE) transporters

Moto Kajiwara, Satohiro Masuda, Shingo Watanabe, Tomohiro Terada, Toshiya Katsura, Ken Ichi Inui

研究成果: Contribution to journalArticle査読

16 被引用数 (Scopus)

抄録

Multidrug and toxin extrusion (MATE) 1 and MATE2-K, H+/organic cation antiporters, are located at the brush-border membrane of renal proximal tubules. The present study aimed to clarify the role of MATE transporters in tubular secretion of varenicline. Varenicline at a dose of 5 mg/kg was administered to wild-type and Mate1-knockout mice via the jugular vein, and its uptake was measured by high-performance liquid chromatography. The renal secretory clearance of and systemic exposure to varenicline were significantly decreased (54.6%, p< 0.05) and increased (116%, p< 0.05) respectively, by the genetic disruption of Mate1 in mice. Uptake of varenicline and [14C]tetraethylammonium (TEA) was examined in HEK293 cells transiently expressing the human (h) MATE1, hMATE2-K, mouse (m) MATE1, and hOCT2 basolateral organic cation transporter. [14C]TEA uptake in HEK293 cells expressing MATE transporters and hOCT2 was decreased in the presence of varenicline. The calculated IC50 values for hMATE1, hMATE2-K, mMATE1, and hOCT2 were 62.2 ± 6.5, 122.3 ± 67.6, 255.0 ± 37.9, and 1,003.9 ± 135.8 (μM; mean ± S.E. for three separate experiments), respectively. Varenicline uptake was significantly increased in HEK293 cells expressing mMATE1, hMATE1, or hMATE2-K cDNA as well as hOCT2 compared to empty vector-transfected cells. In conclusion, renal MATE transporters were found to be responsible for renal tubular secretion of varenicline.

本文言語英語
ページ(範囲)563-569
ページ数7
ジャーナルDrug metabolism and pharmacokinetics
27
6
DOI
出版ステータス出版済み - 2012

All Science Journal Classification (ASJC) codes

  • 薬理学
  • 薬科学
  • 薬理学(医学)

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