Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance.

Lee HH, Leake BF, Teft W, Tirona RG, Kim RB, Ho RH
Mol Cancer Ther. 2015 14 (4): 994-1003

PMID: 25695959 · PMCID: PMC4394048 · DOI:10.1158/1535-7163.MCT-14-0547

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.

©2015 American Association for Cancer Research.

MeSH Terms (18)

Animals Antineoplastic Agents ATP Binding Cassette Transporter, Subfamily B, Member 1 Biological Transport Cell Line, Tumor Docetaxel Humans Liver Liver-Specific Organic Anion Transporter 1 Male Mice Mice, Knockout Organic Anion Transporters Organic Anion Transporters, Sodium-Independent Rats Solute Carrier Organic Anion Transporter Family Member 1B3 Taxoids Tubulin Modulators

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