title: Renal tubular secretion of varenicline by multidrug and toxin extrusion (MATE) transporters.
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 [(14)C]tetraethylammonium (TEA) was examined in HEK293 cells transiently expressing the human (h) MATE1, hMATE2-K, mouse (m) MATE1, and hOCT2 basolateral organic cation transporter. [(14)C]TEA uptake in HEK293 cells expressing MATE transporters and hOCT2 was decreased in the presence of varenicline. The calculated IC(50) 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.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Moto
authors.initials: M
authors.lastname: Kajiwara
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Shingo
authors.initials: S
authors.lastname: Watanabe
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Terada
authors.forename: Toshiya
authors.initials: T
authors.lastname: Katsura
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000097:blood / Q000493:pharmacokinetics*; D001692:Biological Transport; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D011810:Quinoxalines / Q000097:blood / Q000493:pharmacokinetics*; D000068580:Varenicline
chemical_list: D001552:Benzazepines; C514424:MATE1 protein, mouse; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D011810:Quinoxalines; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; D000068580:Varenicline