Abstract 3682: Contribution of hepatic uptake transporters OATP1B1/OATP1B3 to the disposition of docetaxel
Authors: Hye Jeong Lee, Brenda F. Leake, Wendy Teft, Richard B. Kim, Richard H. Ho
Journal: Cancer Research (2014)

Abstract The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug that has been approved for the treatment of multiple malignant diseases, including cancers of the breast, lung, prostate, stomach, and head and neck. Docetaxel is predominantly dependent on hepatic disposition as ∼75% is excreted in bile. While it is known that docetaxel is a substrate of the efflux transporter P-glycoprotein (MDR1; P-gp), less is known regarding transporters that could mediate its cellular uptake and hepatic clearance. Accordingly, screening an array of drug uptake transporters and kinetic analysis for radiolabeled docetaxel transport using a recombinant vaccinia-based method demonstrated that organic anion transporting polypeptides (OATPs), including OATP1A2, OATP1B1 and OATP1B3, were capable of transporting docetaxel in vitro. In addition, an assessment of a panel of single nucleotide polymorphisms (SNPs) in SLCO1B1 revealed that a number of OATP1B1 variants were associated with impaired docetaxel transport. To further evaluate docetaxel transport by OATP1B1 and OATP1B3, we generated MDCKII cells stably expressing MDR1, OATP1B1, OATP1B3, OATP1B1-MDR1, and OATP1B3-MDR1 proteins. Using a transwell system, we then studied intracellular concentrations and transcellular transport after administration of radiolabeled docetaxel to the basal compartment. The transport assay revealed that docetaxel was transported significantly into the apical compartment of double transfected MDCKII-OATP1B1-MDR1/OATP1B3-MDR1 cells compared to the single transfected cells without MDR1 expression up to 3 hours (p &amp;lt; 0.05). Meanwhile, intracellular accumulation of docetaxel was not different between control cells and MDCKII-OATP1B1 or MDCKII-OATP1B3 cells, but was significantly lower in cell lines expressing MDR1 than in cell lines without MDR1 expression (p &amp;lt; 0.05). Consequently, in line with lower intracellular values, higher amounts of docetaxel were found in the apical compartment of cell lines expressing MDR1. Subsequently, we performed in vivo docetaxel transport studies in wild-type and Slco1b2-/- mice (ortholog to hepatic OATP1B1/OATP1B3). There was ∼&amp;gt;5-fold higher plasma concentrations of docetaxel in Slco1b2-/- versus wild-type mice (p &amp;lt; 0.01). The liver-to-plasma ratio of docetaxel was ∼3-fold decreased in Slco1b2-/- mice compared to wild-type mice (p &amp;lt; 0.05). The plasma clearance of docetaxel in Slco1b2-/- mice was 83% lower than wild-type mice (p &amp;lt; 0.05). In conclusion, we demonstrate functional interplay between transporter-mediated uptake and export in docetaxel disposition, suggesting hepatic OATP1B1 and OATP1B3 are important to docetaxel disposition. Moreover, OATP1B1 variants may contribute to the interindividual variability in docetaxel disposition and response. Accordingly, these findings reveal important new insights into the relevance of hepatic OATPs to the clinical pharmacology of docetaxel. Citation Format: Hye Jeong Lee, Brenda F. Leake, Wendy Teft, Richard B. Kim, Richard H. Ho. Contribution of hepatic uptake transporters OATP1B1/OATP1B3 to the disposition of docetaxel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3682. doi:10.1158/1538-7445.AM2014-3682