Predictive Biomarkers and Personalized Medicine Influence of Polymorphic OATP1B-Type Carriers on the Disposition of Docetaxel

Purpose:Docetaxel is extensivelymetabolized byCYP3A4 in the liver butmechanisms bywhich the drug is taken up into hepatocytes remain poorly understood.We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3 and (ii) inherited genetic defects in this process may impair systemic drug elimination. Experimental Design: Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1 1A (wild-type), OATP1B1 5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wild-type and Oatp1b2-knockout mice as well as in two cohorts of patients with multiple variant transporter genotypes (n 1⁄4 213). Results: Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2 but was not transported by OATP1B1 5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P1⁄4 0.0099), which was unrelated to changes in intrinsic metabolic capacity in mouse livermicrosomes. In patients, however, noneof the studied common reduced function variants inOATP1B1 or OATP1B3 were associated with docetaxel clearance (P > 0.05). Conclusions: The existence of at least two potentially redundant uptake transporters in the human liver with similar affinity for docetaxel supports the possibility that functional defects in both of these proteinsmay be required to confer substantially altereddispositionphenotypes. Inviewof theestablished exposure–toxicity relationshipsfordocetaxel,wesuggestthatcautioniswarrantedifdocetaxelhastobeadministeredtogetherwith agents that potently inhibit both OATP1B1 and OATP1B3. Clin Cancer Res; 18(16); 4433–40. 2012 AACR.