P-glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain Disposition and Oral Availability of the Novel Taxane Cabazitaxel (Jevtana) in Mice

Molecular Pharmaceutics
Seng Chuan TangAlfred H Schinkel

Abstract

We aimed to clarify the roles of the multidrug-detoxifying proteins ABCB1, ABCG2, ABCC2, and CYP3A in oral availability and brain accumulation of cabazitaxel, a taxane developed for improved therapy of docetaxel-resistant prostate cancer. Cabazitaxel pharmacokinetics were studied in Abcb1a/1b, Abcg2, Abcc2, Cyp3a, and combination knockout mice. We found that human ABCB1, but not ABCG2, transported cabazitaxel in vitro. Upon oral cabazitaxel administration, total plasma levels were greatly increased due to binding to plasma carboxylesterase Ces1c, which is highly upregulated in several knockout strains. Ces1c inhibition and in vivo hepatic Ces1c knockdown reversed these effects. Correcting for Ces1c effects, Abcb1a/1b, Abcg2, and Abcc2 did not restrict cabazitaxel oral availability, whereas Abcb1a/1b, but not Abcg2, dramatically reduced cabazitaxel brain accumulation (>10-fold). Coadministration of the ABCB1 inhibitor elacridar completely reversed this brain accumulation effect. After correction for Ces1c effects, Cyp3a knockout mice demonstrated a strong (six-fold) increase in cabazitaxel oral availability, which was completely reversed by transgenic human CYP3A4 in intestine and liver. Cabazitaxel markedly inhibited mouse Ces1...Continue Reading

References

Mar 4, 1997·Proceedings of the National Academy of Sciences of the United States of America·A SparreboomO van Tellingen
Dec 5, 1998·Journal of the National Cancer Institute·B Kuska
Mar 21, 2002·Nature Reviews. Cancer·Michael M GottesmanSusan E Bates
Nov 14, 2002·Proceedings of the National Academy of Sciences of the United States of America·Johan W JonkerAlfred H Schinkel
Feb 27, 2003·The Journal of Pharmacology and Experimental Therapeutics·HaiQing DaiWilliam F Elmquist
Apr 28, 2004·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·E M KemperO van Tellingen
Oct 8, 2004·The New England Journal of Medicine·Daniel P PetrylakE David Crawford
May 27, 2005·Cancer Chemotherapy and Pharmacology·Christopher L MortonPhilip M Potter
Apr 14, 2006·The Journal of Pharmacology and Experimental Therapeutics·M L H VlamingA H Schinkel
Oct 26, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jurjen S LagasAlfred H Schinkel
Nov 3, 2007·The Journal of Clinical Investigation·Antonius E van HerwaardenAlfred H Schinkel
Apr 26, 2008·Annals of Oncology : Official Journal of the European Society for Medical Oncology·X PivotJ P Lotz
Jan 17, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Alain C MitaAnthony W Tolcher
Nov 20, 2009·Clinical Pharmacology and Therapeutics·S L W KoolenJ H M Schellens
Dec 24, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jurjen S LagasAlfred H Schinkel
Sep 23, 2010·Nature Reviews. Clinical Oncology·Bostjan SerugaIan F Tannock
Feb 26, 2011·International Journal of Cancer. Journal International Du Cancer·Robert A B van WaterschootAlfred H Schinkel
Jul 27, 2012·Journal of Pharmaceutical Sciences·Fatma Goksin BaharTeruko Imai
Oct 23, 2012·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Johannes MoesBastiaan Nuijen
Oct 24, 2012·International Journal of Cancer. Journal International Du Cancer·Jeroen J M A HendrikxAlfred H Schinkel
Dec 18, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Evita van de SteegAlfred H Schinkel
Dec 20, 2012·Drug Design, Development and Therapy·Jean A Yared, Katherine H R Tkaczuk
Feb 20, 2013·Clinical Pharmacokinetics·Frederik E StuurmanJan H M Schellens
Apr 17, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Patricia VrignaudMarie-Christine Bissery
Apr 15, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Seng Chuan TangAlfred H Schinkel
May 16, 2014·International Journal of Cancer. Journal International Du Cancer·Dilek IusufAlfred H Schinkel
Nov 25, 2014·Molecular Cancer Therapeutics·George E DuranBranimir I Sikic

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Citations

Jul 28, 2016·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Selvi DurmusAlfred H Schinkel
Apr 5, 2017·European Journal of Drug Metabolism and Pharmacokinetics·Ranjeet Prasad DashNuggehally R Srinivas
Jun 15, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Robert S Foti, Deepak K Dalvie
Apr 13, 2018·Nature Reviews. Cancer·Robert W RobeyMichael M Gottesman
Dec 29, 2020·Future Oncology·Marit Ac VermuntJos H Beijnen

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