TY - JOUR
T1 - Renal tubular secretion of varenicline by multidrug and toxin extrusion (MATE) transporters
AU - Kajiwara, Moto
AU - Masuda, Satohiro
AU - Watanabe, Shingo
AU - Terada, Tomohiro
AU - Katsura, Toshiya
AU - Inui, Ken Ichi
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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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U2 - 10.2133/dmpk.DMPK-11-RG-156
DO - 10.2133/dmpk.DMPK-11-RG-156
M3 - Article
C2 - 22510868
AN - SCOPUS:84871696374
SN - 1347-4367
VL - 27
SP - 563
EP - 569
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
IS - 6
ER -