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

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Enomoto A, Takeda M, Shimoda M, Narikawa S, Kobayashi Y, Kobayashi Y, Yamamoto T, Sekine T, Cha SH, Niwa T, Endou H

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

J Pharmacol Exp Ther. 2002 Jun;301(3):797-802.

PubMed ID

12023506 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Probenecid	Solute carrier family 22 member 11	Protein	Humans	Yes	Inhibitor	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Probenecid	Solute carrier family 22 member 11	Protein	Humans	Unknown	Inhibitor	Details
Probenecid	Solute carrier family 22 member 7	Protein	Humans	Unknown	Inhibitor	Details

Polypeptides

Name	UniProt ID
Solute carrier family 22 member 7	Q9Y694	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Probenecid	Solute carrier family 22 member 11	Ki (nM)	54900	N/A	N/A	Details
Probenecid	Solute carrier family 22 member 7	Ki (nM)	766000	N/A	N/A	Details