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

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.

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

“…However, none of these three SNPs were found to have a significant impact on the clearance and other pharmacokinetic parameters of paclitaxel in cancer patients (48). For docetaxel, a potential association between OATP1B3 genotypes and toxicity (leukopenia/neutropenia) has been recently reported in patients (49,50). Additional investigations will be required to validate the clinical relevance of these findings.…”

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

“…67) Considering these findings, Yamada et al constructed a PK/PD model containing the function of OATP1B3 and MRP2 to explain the change of neutrophil count by the administration of docetaxel and found that clinical data were well reproduced by the decreased function of OATP1B3 and MRP2 to 41 and 32%, respectively. 68) Thus, even though SLCO1B3 rs11045585A>G is located in the intronic region and it is difficult to investigate the functional change of OATP1B3 by this mutation in vitro, clinical study with a modeling approach can predict its effect on the transport function quantitatively.…”

Extreme differences in SLCO1B3 functional polymorphisms in Roma and Hungarian populations

“…For the SLCO1B3 intronic SNP, the SLCO1B3 1683-5676G allele frequency and the GG homozygous variant genotype were nearly 5-fold increased in Hungarians compared to Roma population. Subsequently, in Hungarians, the elevated rate of rs11045585 variant may contribute the decreased OATP1B3 function leading to potential modification in therapeutic efficacy (Yamada et al, 2014). Compared the allele frequencies of SLCO1B3 c.1683-5676A>G and c.334T>G polymorphisms to data from the HapMap project are presented in Table 4.…”