title: Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance.
abstract: The organic anion-transporting polypeptides represent an important family of drug uptake transporters that mediate the cellular uptake of a broad range of substrates including numerous drugs. Doxorubicin is a highly efficacious and well-established anthracycline chemotherapeutic agent commonly used in the treatment of a wide range of cancers. Although doxorubicin is a known substrate for efflux transporters such as P-glycoprotein (P-gp; MDR1, ABCB1), significantly less is known regarding its interactions with drug uptake transporters. Here, we investigated the role of organic anion transporting polypeptide (OATP) transporters to the disposition of doxorubicin. A recombinant vaccinia-based method for expressing uptake transporters in HeLa cells revealed that OATP1A2, but not OATP1B1 or OATP1B3, and the rat ortholog Oatp1a4 were capable of significant doxorubicin uptake. Interestingly, transwell assays using Madin-Darby canine kidney II cell line cells stably expressing specific uptake and/or efflux transporters revealed that OATP1B1, OATP1B3, and OATP1A2, either alone or in combination with MDR1, significantly transported doxorubicin. An assessment of polymorphisms in SLCO1A2 revealed that four variants were associated with significantly impaired doxorubicin transport in vitro. In vivo doxorubicin disposition studies revealed that doxorubicin plasma area under the curve was significantly higher (1.7-fold) in Slco1a/1b-/-versus wild-type mice. The liver-to-plasma ratio of doxorubicin was significantly decreased (2.3-fold) in Slco1a/1b2-/-mice and clearance was reduced by 40% compared with wild-type mice, suggesting Oatp1b transporters are important for doxorubicin hepatic uptake. In conclusion, we demonstrate important roles for OATP1A/1B in transporter-mediated uptake and disposition of doxorubicin.
authors: Division of Hematology and Oncology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee (H.H.L., B.F.L., R.H.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada (R.B.K.).
authors: Hannah H
authors: HH
authors: Lee
authors: Division of Hematology and Oncology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee (H.H.L., B.F.L., R.H.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada (R.B.K.).
authors: Brenda F
authors: BF
authors: Leake
authors: Division of Hematology and Oncology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee (H.H.L., B.F.L., R.H.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada (R.B.K.).
authors: Richard B
authors: RB
authors: Kim
authors: Division of Hematology and Oncology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee (H.H.L., B.F.L., R.H.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada (R.B.K.) Richard.ho@vanderbilt.edu.
authors: Richard H
authors: RH
authors: Ho
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D004285:Dogs; D004317:Doxorubicin / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D051381:Rats; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004317:Doxorubicin; D027381:Liver-Specific Organic Anion Transporter 1; D050505:Mutant Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; C572127:SLCO1A1 protein, mouse; C512988:SLCO1A2 protein, human; C498887:Slco1b2 protein, mouse