title: Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance.
abstract: The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug for the treatment of multiple solid tumors and is predominantly dependent on hepatic disposition. In this study, we evaluated drug uptake transporters capable of transporting radiolabeled docetaxel. By screening an array of drug uptake transporters in HeLa cells using a recombinant vaccinia-based method, five organic anion-transporting polypeptides (OATP) capable of docetaxel uptake were identified: OATP1A2, OATP1B1, OATP1B3, OATP1C1, and Oatp1b2. Kinetic analysis of docetaxel transport revealed similar kinetic parameters among hepatic OATP1B/1b transporters. An assessment of polymorphisms (SNPs) in SLCO1B1 and SLCO1B3 revealed that a number of OATP1B1 and OATP1B3 variants were associated with impaired docetaxel transport. A Transwell-based vectorial transport assay using MDCKII stable cells showed that docetaxel was transported significantly into the apical compartment of double-transfected (MDCKII-OATP1B1/MDR1 and MDCKII-OATP1B3/MDR1) cells compared with single-transfected (MDCKII-OATP1B1 and MDCKII-OATP1B3) cells (P < 0.05) or control (MDCKII-Co) cells (P < 0.001). In vivo docetaxel transport studies in Slco1b2(-/-) mice showed approximately >5.5-fold higher plasma concentrations (P < 0.01) and approximately 3-fold decreased liver-to-plasma ratio (P < 0.05) of docetaxel compared with wild-type (WT) mice. The plasma clearance of docetaxel in Slco1b2(-/-) mice was 83% lower than WT mice (P < 0.05). In conclusion, this study demonstrates the important roles of OATP1B transporters to the hepatic disposition and clearance of docetaxel, and supporting roles of these transporters for docetaxel pharmacokinetics.
authors.affiliation: Division of Hematology and Oncology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Hannah H
authors.initials: HH
authors.lastname: Lee
authors.affiliation: Division of Hematology and Oncology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Leake
authors.affiliation: Division of Clinical Pharmacology, Schulich School of Medicine and Dentistry, Western University/University of Western Ontario, London, Ontario, Canada.
authors.forename: Wendy
authors.initials: W
authors.lastname: Teft
authors.affiliation: Division of Clinical Pharmacology, Schulich School of Medicine and Dentistry, Western University/University of Western Ontario, London, Ontario, Canada.
authors.forename: Rommel G
authors.initials: RG
authors.lastname: Tirona
authors.affiliation: Division of Clinical Pharmacology, Schulich School of Medicine and Dentistry, Western University/University of Western Ontario, London, Ontario, Canada.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
authors.affiliation: Division of Hematology and Oncology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee. richard.ho@vanderbilt.edu.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Ho
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001692:Biological Transport; D045744:Cell Line, Tumor; D000077143:Docetaxel; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000172:deficiency / Q000378:metabolism; D051381:Rats; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D043823:Taxoids / Q000378:metabolism* / Q000493:pharmacokinetics; D050257:Tubulin Modulators / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C498887:Slco1b2 protein, mouse; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D043823:Taxoids; D050257:Tubulin Modulators; D000077143:Docetaxel