Kinetic Interpretation of the Importance of OATP1B3 and MRP2 in Docetaxel-Induced Hematopoietic Toxicity

A Yamada; K Maeda; K Kiyotani; T Mushiroda; Y Nakamura; Y Sugiyama

doi:10.1038/psp.2014.23

Kinetic Interpretation of the Importance of OATP1B3 and MRP2 in Docetaxel-Induced Hematopoietic Toxicity

CPT Pharmacometrics Syst Pharmacol. 2014 Jul 23;3(7):e126. doi: 10.1038/psp.2014.23.

Authors

A Yamada¹, K Maeda¹, K Kiyotani², T Mushiroda³, Y Nakamura⁴, Y Sugiyama⁵

Affiliations

¹ Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
² 1] Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan [2] Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
³ Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.
⁴ 1] Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-ku, Bunkyo-ku, Tokyo, Japan [2] Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
⁵ Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Research Cluster for Innovation, RIKEN, Tsurumi-ku, Yokohama City, Kanagawa, Japan.

Abstract

Neutropenia is a lethal dose-limiting toxicity of docetaxel. Our previous report indicated that the prevalence of severe docetaxel-induced neutropenia is significantly associated with genetic polymorphisms in solute carrier organic anion transporter 1B3 (SLCO1B3) (encoding organic anion-transporting polypeptide 1B3 (OATP1B3)) and ATP-binding cassette subfamily C2 (ABCC2) (encoding multidrug-resistant-associated protein 2 (MRP2)). Therefore, we investigated their significance in docetaxel-induced neutropenia. In vitro experiments suggested their possible involvement in the hepatic uptake of docetaxel and its efflux from bone marrow cells. To further characterize a quantitative impact of OATP1B3 and MRP2 on neutropenia, we used an in silico simulation of the neutrophil count in docetaxel-treated subjects with functional changes in OATP1B3 and MRP2 in a pharmacokinetic/pharmacodynamic model. The clinically reported odds ratios for docetaxel-induced neutropenia risk were explained by the decreased function of OATP1B3 and MRP2 to 41 and 32%, respectively. These results suggest that reduced activities of OATP1B3 and MRP2 associated with systemic exposure and local accumulation in bone marrow cells, respectively, account for the docetaxel-induced neutropenia observed clinically.