title: P-glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain Disposition and Oral Availability of the Novel Taxane Cabazitaxel (Jevtana) in Mice.
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 Ces1c, but human CES1 and CES2 only weakly. Ces1c upregulation can thus complicate preclinical cabazitaxel studies. In summary, ABCB1 limits cabazitaxel brain accumulation and therefore potentially therapeutic efficacy against (micro)metastases or primary tumors positioned wholly or partly behind a functional blood-brain barrier. This can be reversed with elacridar coadministration, and similar effects may apply to ABCB1-expressing tumors. CYP3A4 profoundly reduces the oral availability of cabazitaxel. This may potentially be greatly improved by coadministering ritonavir or other CYP3A inhibitors, suggesting the option of patient-friendly oral cabazitaxel therapy.
authors: Department of Molecular Oncology, The Netherlands Cancer Institute , 1066 CX Amsterdam, The Netherlands.
authors: Seng Chuan
authors: SC
authors: Tang
authors: Department of Molecular Oncology, The Netherlands Cancer Institute , 1066 CX Amsterdam, The Netherlands.|Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek , 1066 CX Amsterdam, The Netherlands.
authors: Anita
authors: A
authors: Kort
authors: Department of Thrombosis and Hemostasis, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , 2333 ZA Leiden, The Netherlands.
authors: Ka Lei
authors: KL
authors: Cheung
authors: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek , 1066 CX Amsterdam, The Netherlands.
authors: Hilde
authors: H
authors: Rosing
authors: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University , Kakuma-machi, Kanazawa 920-1192, Japan.
authors: Tatsuki
authors: T
authors: Fukami
authors: Department of Molecular Oncology, The Netherlands Cancer Institute , 1066 CX Amsterdam, The Netherlands.
authors: Selvi
authors: S
authors: Durmus
authors: Department of Molecular Oncology, The Netherlands Cancer Institute , 1066 CX Amsterdam, The Netherlands.
authors: Els
authors: E
authors: Wagenaar
authors: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek , 1066 CX Amsterdam, The Netherlands.
authors: Jeroen J M A
authors: JJ
authors: Hendrikx
authors: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University , Kakuma-machi, Kanazawa 920-1192, Japan.
authors: Miki
authors: M
authors: Nakajima
authors: Department of Thrombosis and Hemostasis, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , 2333 ZA Leiden, The Netherlands.
authors: Bart J M
authors: BJ
authors: van Vlijmen
authors: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek , 1066 CX Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University , 3512 JE Utrecht, The Netherlands.
authors: Jos H
authors: JH
authors: Beijnen
authors: Department of Molecular Oncology, The Netherlands Cancer Institute , 1066 CX Amsterdam, The Netherlands.
authors: Alfred H
authors: AH
authors: Schinkel
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D001923:Brain Chemistry; D043182:Carboxylesterase / Q000097:blood*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004285:Dogs; D061985:Madin Darby Canine Kidney Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D043823:Taxoids / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*
chemical_list: C000715087:ABCC2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D043823:Taxoids; C552428:cabazitaxel; D051544:Cytochrome P-450 CYP3A; D002265:Carboxylic Ester Hydrolases; C545375:carboxylesterase 1, mouse; D043182:Carboxylesterase
keywords: P-glycoprotein; brain accumulation; cabazitaxel; carboxylesterase; pharmacokinetics