RT Journal Article
SR Electronic
T1 Characterization of the Uptake of Organic Anion Transporter (OAT) 1 and OAT3 Substrates by Human Kidney Slices
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 362
OP 369
DO 10.1124/jpet.106.113076
VO 321
IS 1
A1 Nozaki, Yoshitane
A1 Kusuhara, Hiroyuki
A1 Kondo, Tsunenori
A1 Hasegawa, Maki
A1 Shiroyanagi, Yoshiyuki
A1 Nakazawa, Hayakazu
A1 Okano, Teruo
A1 Sugiyama, Yuichi
YR 2007
UL http://jpet.aspetjournals.org/content/321/1/362.abstract
AB The activities of renal multispecific organic anion transporters (OATs) 1 and 3 have not been fully evaluated in human kidneys. In the present study, the uptake of some organic anions was characterized in kidney slices from human intact renal cortical tissues: hOAT1 and hOAT3 substrates [p-aminohippurate (PAH) and 2,4-dichlorophenoxyacetate (2,4-D)] and hOAT3 substrates [benzylpenicillin (PCG), dehydroepiandrosterone sulfate (DHEAS), and estrone sulfate (ES)]. Despite large interbatch differences, hOAT1 and hOAT3 mRNA levels correlated well, and there was a good correlation between the uptake of PAH and PCG by kidney slices. The uptake of organic anions by kidney slices was saturable with Km values of 31 to 48 μM for PAH, 0.73 to 4.9 μM for 2,4-D, 14 to 90 μM for PCG, and 9.2 to 11 μM for ES. These parameters were comparable with those for hOAT1 and/or hOAT3. The uptake of DHEAS consists of two saturable components with Km values of 2.2 to 3.9 and 1300 μM, and the Km value of the high-affinity component was close to that for hOAT3. Furthermore, PAH more potently inhibited the uptake of 2,4-D than that of PCG and DHEAS. PCG had a weaker effect on the uptake of PAH and 2,4-D than expected from its Km value. Taken together, it is likely that the uptake of PAH and 2,4-D is due to OAT1, and the uptake of PCG and ES and part of DHEAS uptake are due to OAT3 in human kidney slices. Human kidney slices are useful tools for characterizing the renal uptake of drugs. The American Society for Pharmacology and Experimental Therapeutics