Involvement of multiple efflux transporters in hepatic disposition of fexofenadine.
Fexofenadine (FEX) is mainly eliminated from the liver into bile in unchanged form. We demonstrated previously that organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are involved in the hepatic uptake of FEX. However, little is known about the mechanisms controlling the hepatic efflux of FEX from the liver to bile and blood. In the present study, the involvement of hepatic efflux transporters in the pharmacokinetics of FEX was investigated in both in vitro and in vivo studies. Vectorial transport of FEX was observed in OATP1B3/human bile salt export pump (hBSEP) double transfectants but not in OATP1B3/human breast cancer resistance protein double transfectants, which indicates the possible contribution of hBSEP to the biliary excretion of FEX in humans. In multidrug resistance-associated protein 2 (Mrp2)(-/-) mice, the biliary excretion clearance based on the plasma concentration and the liver-to-plasma concentration ratio significantly decreased, whereas the biliary excretion clearance based on the liver concentration decreased only with 20%, suggesting the minimum contribution of Mrp2 to its biliary excretion. ATP-dependent transport of FEX was observed in hMRP3-enriched membrane vesicles but not hMRP4. In Mrp3(-/-) mice, the biliary excretion clearance based on both the plasma and liver concentration and the liver-to-plasma concentration ratio increased, suggesting the significant contribution of Mrp3 to its sinusoidal efflux and the up-regulation of its biliary excretion in Mrp3(-/-) mice. On the other hand, pharmacokinetics of FEX remained unchanged in Mrp4(-/-) mice. This information provides a novel insight into the transporters important for FEX disposition.
Matsushima
Soichiro
S
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Maeda
Kazuya
K
Hayashi
Hisamitsu
H
Debori
Yasuyuki
Y
Schinkel
Alfred H
AH
Schuetz
John D
JD
Kusuhara
Hiroyuki
H
Sugiyama
Yuichi
Y
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D004285:Dogs; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D001647:Bile Acids and Salts; D005978:Glutathione; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011804:Quinolines; D011994:Recombinant Proteins; D016593:Terfenadine; C093491:ABCB11 protein, human; C000715087:ABCC2 protein, human; C073492:ABCC4 protein, human; C114462:multidrug resistance-associated protein 3; C093230:fexofenadine; C108475:pitavastatin