Vectorial transport of enalapril by Oatp1a1/Mrp2 and OATP1B1 and OATP1B3/MRP2 in rat and human livers.
Although Oatp1a1 (rat organic anion-transporting polypeptide 1a1) was the transporter found responsible for the hepatocellular entry of enalapril (EN) into the rat liver, the canalicular transporter involved for excretion of EN and the metabolite, enalaprilat (ENA), was unknown. The Eisai hyperbilirubinemic rat (EHBR) that lacks Mrp2 (multidrug resistance-associated protein 2) was used to appraise the role of Mrp2 in the excretion of [3H]EN and its metabolite [3H]ENA in single-pass rat liver preparations. Although the total and metabolic clearances and hepatic extraction ratios at steady-state were virtually unaltered for EN in EHBR compared with published values of Sprague-Dawley rats, the biliary clearances of EN and ENA were significantly reduced almost to zero (P<0.05). Involvement of human OATP1B1, OATP1B3, and MRP2 in EN transport was further assessed in single- or double-transfected mammalian cells. Human embryonic kidney 293 cells that expressed OATP1B1 or OATP1B3 showed that OATP1B3 transport of EN (20-500 microM) was of low affinity, whereas transport of EN by OATP1B1 was associated with the Km of 262+/-35 microM, a value similar to that for Oatp1a1 (214 microM). The transcellular transport of EN via human OATP1B1 and MRP2, investigated with the double-transfected Madin-Darby canine kidney (MDCK) II cells in the Transwell system, showed that the sinusoidal to canalicular flux of EN in the OATP1B1/MRP2/MDCK cells was significantly higher (P<0.05) than that of mock/MDCK and OATP1B1/MDCK cells. EN was transported by Oatp1a1 and Mrp2 in rats and OATP1B1/OATP1B3 and MRP2 in humans.
Liu
Lichuan
L
Department of Pharmaceutical Sciences, University of Toronto, 19 Russell Street, Toronto, ON, Canada M5S 2S2, and Division of Tumor Biochemistry, German Cancer Research Center, Heidelberg, Germany.
Cui
Yunhai
Y
Chung
Alfred Y
AY
Shitara
Yoshihisa
Y
Sugiyama
Yuichi
Y
Keppler
Dietrich
D
Pang
K Sandy
KS
D000818:Animals; D002417:Cattle; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
D004656:Enalapril; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C421043:Slc22a6 protein, rat