Interactions of human organic anion transporters with diuretics.
The tubular secretion of diuretics in the proximal tubule has been shown to be critical for the action of drugs. To elucidate the molecular mechanisms for the tubular excretion of diuretics, we have elucidated the interactions of human organic anion transporters (hOATs) with diuretics using cells stably expressing hOATs. Diuretics tested were thiazides, including chlorothiazide, cyclothiazide, hydrochlorothiazide, and trichlormethiazide; loop diuretics, including bumetanide, ethacrynic acid, and furosemide; and carbonic anhydrase inhibitors, including acetazolamide and methazolamide. These diuretics inhibited organic anion uptake mediated by hOAT1, hOAT2, hOAT3, and hOAT4 in a competitive manner. hOAT1 exhibited the highest affinity interactions for thiazides, whereas hOAT3 did those for loop diuretics. hOAT1, hOAT3, and hOAT4 but not hOAT2, mediated the uptake of bumetanide. hOAT3 and hOAT4, but not hOAT1 mediated the efflux of bumetanide. hOAT1 and hOAT3, but not hOAT2 and hOAT4 mediated the uptake of furosemide. In conclusion, it was suggested that hOAT1 may play an important role in the basolateral uptake of thiazides, and hOAT3 in the uptake of loop diuretics. In addition, it was also suggested that bumetanide taken up by hOAT3 and/or hOAT1 is excreted into the urine by hOAT4.
Hasannejad
Habib
H
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan.
Takeda
Michio
M
Taki
Kentarou
K
Shin
Ho Jung
HJ
Babu
Ellappan
E
Jutabha
Promsuk
P
Khamdang
Suparat
S
Aleboyeh
Mahmoud
M
Onozato
Maristela Lika
ML
Tojo
Akihiro
A
Enomoto
Atsushi
A
Anzai
Naohiko
N
Narikawa
Shinichi
S
Huang
Xiu-Lin
XL
Niwa
Toshimitsu
T
Endou
Hitoshi
H
D000818:Animals; D001692:Biological Transport; D002034:Bumetanide / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004232:Diuretics / Q000493:pharmacokinetics*; D005665:Furosemide / Q000032:analysis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D027361:Organic Anion Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D004232:Diuretics; D027361:Organic Anion Transporters; D002034:Bumetanide; D005665:Furosemide