Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors.
The organic anion transport system is involved in the tubular excretion and reabsorption of various drugs and substances. The purpose of this study was to characterize the effects of various organic anion transport inhibitors on renal organic anion transport using proximal tubule cells stably expressing human organic anion transporter 2 (hOAT2) and hOAT4. Immunohistochemical analysis revealed that hOAT2 is localized to the basolateral side of the proximal tubule in the kidney. hOAT2 mediated a time- and concentration-dependent increase in prostaglandin F(2alpha) (PGF(2alpha)) uptake. The organic anion transport inhibitors used for this study were probenecid, 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902), betamipron, and cilastatin. Probenecid, but not KW-3902, betamipron, and cilastatin, significantly inhibited hOAT2-mediated PGF(2alpha) uptake. In contrast, probenecid, KW-3902, and betamipron, but not cilastatin, inhibited hOAT4-mediated estrone sulfate (ES) uptake. Kinetic analyses revealed that these inhibitions were competitive. The K(i) value of probenecid for hOAT2 was 766 microM, whereas those of probenecid, KW-3902, and betamipron for hOAT4 were 54.9, 20.7, and 502 microM, respectively. These results suggest that probenecid, KW-3902, and betamipron could inhibit hOAT4-mediated ES uptake in vitro, whereas probenecid alone could inhibit the hOAT2-mediated PGF(2alpha) uptake. Comparing the K(i) values with the therapeutically relevant concentrations of unbound inhibitors in the plasma, probenecid alone was predicted to inhibit hOAT4-mediated organic anion transport in vivo.
Enomoto
Atsushi
A
Department of Clinical Preventive Medicine, Nagoya University School of Medicine, Nagoya, Japan.
Takeda
Michio
M
Shimoda
Minoru
M
Narikawa
Shinichi
S
Kobayashi
Yukari
Y
Kobayashi
Yasuna
Y
Yamamoto
Toshinori
T
Sekine
Takashi
T
Cha
Seok Ho
SH
Niwa
Toshimitsu
T
Endou
Hitoshi
H
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D015237:Dinoprost / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats
D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C427207:SLC22A11 protein, human; C490280:SLC22A7 protein, human; C490281:Slc22a7 protein, mouse; C088800:Slc22a7 protein, rat; D015237:Dinoprost