title: Influence of drug formulation on OATP1B-mediated transport of paclitaxel.
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.
authors.affiliation: 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.
authors.forename: Annemieke J M
authors.initials: AJ
authors.lastname: Nieuweboer
authors.affiliation: 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.
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Chunshan
authors.initials: C
authors.lastname: Gui
authors.affiliation: 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Hagenbuch
authors.affiliation: 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.
authors.forename: Inge M
authors.initials: IM
authors.lastname: Ghobadi Moghaddam-Helmantel
authors.affiliation: 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.
authors.forename: Alice A
authors.initials: AA
authors.lastname: Gibson
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: de Bruijn
authors.affiliation: 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.
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: 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.
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects*; D001952:Bridged-Ring Compounds / Q000378:metabolism / Q000493:pharmacokinetics; D016466:CHO Cells; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003412:Cricetulus; D000077143:Docetaxel; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000378:metabolism* / Q000493:pharmacokinetics*; D043823:Taxoids / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D043823:Taxoids; D000077143:Docetaxel; C080625:taxane; C552428:cabazitaxel; D017239:Paclitaxel
references.citation: Cancer Chemother Pharmacol. 1999;43(1):13-8
references.pmid: 9923536
references.citation: Biomed Pharmacother. 2011 Sep;65(6):417-26
references.pmid: 21719246
references.citation: Clin Cancer Res. 2006 Feb 15;12(4):1317-24
references.pmid: 16489089
references.citation: Pharm Res. 2012 Oct;29(10):2833-44
references.pmid: 22588463
references.citation: Cancer Biol Ther. 2005 Aug;4(8):815-8
references.pmid: 16210916
references.citation: Br J Cancer. 1999 Sep;81(2):330-5
references.pmid: 10496361
references.citation: Expert Opin Drug Deliv. 2012 Aug;9(8):975-90
references.pmid: 22703284
references.citation: Cancer Lett. 2008 Feb 18;260(1-2):163-9
references.pmid: 18082941
references.citation: Trends Pharmacol Sci. 2012 Feb;33(2):100-8
references.pmid: 22130008
references.citation: Pharmacogenomics. 2011 Jul;12(7):1017-37
references.pmid: 21787191
references.citation: J Pharm Pharmacol. 2009 Aug;61(8):1029-35
references.pmid: 19703346
references.citation: Mol Pharmacol. 2008 Aug;74(2):320-9
references.pmid: 18413659
references.citation: Cancer Biol Ther. 2006 Jul;5(7):833-9
references.pmid: 16775418
references.citation: Clin Cancer Res. 1999 Oct;5(10):2918-24
references.pmid: 10537361
references.citation: Cancer Chemother Pharmacol. 2001 Apr;47(4):309-18
references.pmid: 11345647
references.citation: Clin Cancer Res. 2008 Jul 1;14(13):4200-5
references.pmid: 18594000
references.citation: Clin Pharmacol Ther. 2007 Jan;81(1):76-82
references.pmid: 17186002
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):2031-5
references.pmid: 9050899
references.citation: Expert Opin Drug Deliv. 2013 Mar;10(3):325-40
references.pmid: 23289542
references.citation: Clin Cancer Res. 2012 Aug 15;18(16):4433-40
references.pmid: 22711709
references.citation: Br J Pharmacol. 2012 Mar;165(6):1836-1847
references.pmid: 21923755
references.citation: Cancer Res. 1999 Apr 1;59(7):1454-7
references.pmid: 10197613
references.citation: Pharmacol Rev. 2013 May 17;65(3):944-66
references.pmid: 23686349
references.citation: Am J Physiol Cell Physiol. 2013 Dec 15;305(12):C1223-9
references.pmid: 23986199
references.citation: Clin Cancer Res. 2013 Jun 1;19(11):2973-83
references.pmid: 23589177
references.citation: Mol Pharm. 2012 Sep 4;9(9):2577-81
references.pmid: 22808947
references.citation: Cancer Res. 1996 May 1;56(9):2112-5
references.pmid: 8616858
references.citation: Pharmacol Res. 2009 Jul;60(1):50-6
references.pmid: 19427586
references.citation: J Clin Oncol. 2001 Oct 15;19(20):4065-73
references.pmid: 11600609
references.citation: Pharm Res. 2005 Jun;22(6):867-74
references.pmid: 15948030
references.citation: Ann Oncol. 2006 May;17(5):735-49
references.pmid: 16364960
references.citation: Eur J Pharmacol. 2008 Apr 14;584(1):57-65
references.pmid: 18321482
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2013 Aug 1;932:74-5
references.pmid: 23831699
references.citation: J Control Release. 2013 Sep 28;170(3):365-72
references.pmid: 23770008
references.citation: Toxicol Sci. 2006 May;91(1):140-9
references.pmid: 16495352
references.citation: Gut. 2014 Jun;63(6):974-83
references.pmid: 24067278
references.citation: Clin Pharmacokinet. 2005;44(4):349-66
references.pmid: 15828850
references.citation: Clin Cancer Res. 2013 Feb 15;19(4):821-32
references.pmid: 23243220
references.citation: Br J Pharmacol. 2012 Mar;165(5):1260-87
references.pmid: 22013971
references.citation: Eur J Cancer. 2006 Aug;42(12):1789-96
references.pmid: 16750622
references.citation: Clin Pharmacokinet. 2003;42(7):665-85
references.pmid: 12844327
references.citation: Clin Pharmacol Ther. 2011 Jun;89(6):798-805
references.pmid: 21471963
references.citation: Clin Cancer Res. 2011 Jan 15;17(2):294-301
references.pmid: 21097690
references.citation: Drug Metab Pharmacokinet. 2009;24(5):418-27
references.pmid: 19881253
references.citation: Proc Soc Exp Biol Med. 1950 Oct;75(1):16-20
references.pmid: 14797719
references.citation: Pharm Res. 2014 Jan;31(1):204-15
references.pmid: 23921491
references.citation: Mol Cancer Ther. 2013 Aug;12(8):1537-44
references.pmid: 23757163