title: In vivo disposition of doxorubicin is affected by mouse Oatp1a/1b and human OATP1A/1B transporters.
abstract: Organic anion-transporting polypeptides (OATPs) are important drug uptake transporters, mediating distribution of substrates to several pharmacokinetically relevant organs. Doxorubicin is a widely used anti-cancer drug extensively studied for its interactions with various drug transporters, but not OATPs. Here, we investigated the role of OATP1A/1B proteins in the distribution of doxorubicin. In vitro, we observed ∼ 2-fold increased doxorubicin uptake in HEK293 cells overexpressing human OATP1A2, but not OATP1B1 or OATP1B3. In mice, absence of Oatp1a/1b transporters led to up to 2-fold higher doxorubicin plasma concentrations and 1.3-fold higher plasma AUC. Conversely, liver AUC and liver-to-plasma ratios of Oatp1a/1b(-/-) mice were 1.4-fold and up to 4.1-fold lower than in wild-type mice, respectively. Decreased doxorubicin levels in the small intestinal content reflected those in the liver, indicating a reduced biliary excretion of doxorubicin in Oatp1a/1b(-/-) mice. These results demonstrate important control of doxorubicin plasma clearance and hepatic uptake by mouse Oatp1a/1b transporters. This is unexpected, as the fairly hydrophobic weak base doxorubicin is an atypical OATP1A/1B substrate. Interestingly, transgenic liver-specific expression of human OATP1A2, OATP1B1 or OATP1B3 could partially rescue the increased doxorubicin plasma levels of Oatp1a/1b(-/-) mice. Hepatic uptake and bile-derived intestinal excretion of doxorubicin were completely reverted to wild-type levels by OATP1A2, and partially by OATP1B1 and OATP1B3. Thus, doxorubicin is transported by hepatocyte-expressed OATP1A2, -1B1 and -1B3 in vivo, illustrating an unexpectedly wide substrate specificity. These findings have possible implications for the uptake, disposition, therapy response and toxicity of doxorubicin, also in human tumors and tissues expressing these transporters.
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Selvi
authors.initials: S
authors.lastname: Durmus
authors.forename: Jyoti
authors.initials: J
authors.lastname: Naik
authors.forename: Levi
authors.initials: L
authors.lastname: Buil
authors.forename: Els
authors.initials: E
authors.lastname: Wagenaar
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001692:Biological Transport; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D051379:Mice; D008822:Mice, Transgenic; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000502:physiology*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C572127:SLCO1A1 protein, mouse; C512988:SLCO1A2 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human
keywords: OATP; doxorubicin; hepatic uptake; pharmacokinetics