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 <i>in vitro</i>. 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 <i>in vivo</i> 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