Open AccessKinetic Interpretation of the Importance of OATP1B3 and MRP2 in Docetaxel‐Induced Hematopoietic Toxicity
Author(s) -
Yamada A,
Maeda K,
Kiyotani K,
Mushiroda T,
Nakamura Y,
Sugiyama Y
Publication year - 2014
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1038/psp.2014.23
Subject(s) - docetaxel , neutropenia , multidrug resistance associated protein 2 , pharmacology , bone marrow , toxicity , medicine , pharmacokinetics , chemistry , transporter , endocrinology , biochemistry , atp binding cassette transporter , chemotherapy , gene
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. CPT Pharmacometrics Syst. Pharmacol . (2014) 3, e126; doi: 10.1038/psp.2014.23 ; published online 23 July 2014