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

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)563-569
Number of pages7
JournalDrug metabolism and pharmacokinetics
Volume27
Issue number6
DOIs
Publication statusPublished - Jan 1 2012
Externally publishedYes

Fingerprint

Kidney
HEK293 Cells
Tetraethylammonium
Cations
Antiporters
Proximal Kidney Tubule
Jugular Veins
Microvilli
Varenicline
Knockout Mice
Inhibitory Concentration 50
Complementary DNA
High Pressure Liquid Chromatography
Membranes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

Cite this

Renal tubular secretion of varenicline by multidrug and toxin extrusion (MATE) transporters. / Kajiwara, Moto; Masuda, Satohiro; Watanabe, Shingo; Terada, Tomohiro; Katsura, Toshiya; Inui, Ken Ichi.

In: Drug metabolism and pharmacokinetics, Vol. 27, No. 6, 01.01.2012, p. 563-569.

Research output: Contribution to journalArticle

Kajiwara, Moto ; Masuda, Satohiro ; Watanabe, Shingo ; Terada, Tomohiro ; Katsura, Toshiya ; Inui, Ken Ichi. / Renal tubular secretion of varenicline by multidrug and toxin extrusion (MATE) transporters. In: Drug metabolism and pharmacokinetics. 2012 ; Vol. 27, No. 6. pp. 563-569.
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abstract = "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.",
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