RT Journal Article
SR Electronic
T1 Interaction of Human Organic Anion Transporters 2 and 4 with Organic Anion Transport Inhibitors
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 797
OP 802
DO 10.1124/jpet.301.3.797
VO 301
IS 3
A1 Atsushi Enomoto
A1 Michio Takeda
A1 Minoru Shimoda
A1 Shinichi Narikawa
A1 Yukari Kobayashi
A1 Yasuna Kobayashi
A1 Toshinori Yamamoto
A1 Takashi Sekine
A1 Seok Ho Cha
A1 Toshimitsu Niwa
A1 Hitoshi Endou
YR 2002
UL http://jpet.aspetjournals.org/content/301/3/797.abstract
AB 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 F2α (PGF2α) 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 PGF2α 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. TheKi value of probenecid for hOAT2 was 766 μM, whereas those of probenecid, KW-3902, and betamipron for hOAT4 were 54.9, 20.7, and 502 μM, 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 PGF2α uptake. Comparing theKi 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. The American Society for Pharmacology and Experimental Therapeutics