Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors

被引:149
作者
Enomoto, A
Takeda, M
Shimoda, M
Narikawa, S
Kobayashi, Y
Kobayashi, Y
Yamamoto, T
Sekine, T
Cha, SH
Niwa, T
Endou, H
机构
[1] Kyorin Univ, Sch Med, Dept Pharmacol & Toxicol, Mitaka, Tokyo 181, Japan
[2] Nagoya Univ, Sch Med, Dept Clin Prevent Med, Nagoya, Aichi 466, Japan
[3] Tokyo Univ Agr & Technol, Fac Agr, Dept Vet Med, Tokyo, Japan
[4] Showa Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Tokyo 142, Japan
关键词
D O I
10.1124/jpet.301.3.797
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 muM, whereas those of probenecid, KW-3902, and betamipron for hOAT4 were 54.9, 20.7, and 502 muM, 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.
引用
收藏
页码:797 / 802
页数:6
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