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.