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Cancer Res. 2014 Jun 1;74(11):3137-45. doi: 10.1158/0008-5472.CAN-13-3634. Epub 2014 Apr 22.

Influence of drug formulation on OATP1B-mediated transport of paclitaxel.

Author information

1
Authors' Affiliations: Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Missouri.
2
Authors' Affiliations: Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Missouri a.mathijssen@erasmusmc.nl.
3
Authors' Affiliations: Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, MissouriAuthors' Affiliations: Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Missouri.

Abstract

Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters before metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent OATP1B2. Pharmacokinetic studies were done in wild-type and OATP1B2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and OATP1B2, and these in vitro transport processes were strongly reduced in the presence of clinically relevant concentrations of PS80 and CrEL. When paclitaxel was administered without any solubilizers, deficiency of OATP1B2 in mice was associated with a significantly decreased systemic clearance because of a liver distribution defect (P=0.000484). However, this genotype dependence of paclitaxel clearance was masked in the presence of PS80 or CrEL because of significant inhibition of OATP1B2-mediated hepatocellular uptake of the drug (P<0.05). Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes and indicate that this process can be inhibited by PS80 and CrEL. These results suggest that the likelihood of drug-drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer.

PMID:
24755470
PMCID:
PMC4161133
DOI:
10.1158/0008-5472.CAN-13-3634
[Indexed for MEDLINE]
Free PMC Article

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