5 research outputs found
Oral Availability and Brain Penetration of the BâRAF<sup>V600E</sup> Inhibitor Vemurafenib Can Be Enhanced by the PâGlycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Inhibitor Elacridar
Vemurafenib (PLX4032) is a novel tyrosine kinase inhibitor
that
has clinical efficacy against metastatic melanoma harboring a BRAF<sup>V600E</sup> mutation. We aimed to establish whether oral availability
and brain penetration of vemurafenib could be restricted by the multidrug
efflux transporters P-glycoprotein (P-gp/ABCB1) and breast cancer
resistance protein (BCRP/ABCG2), as these might limit therapeutic
efficacy, especially against brain metastases. <i>In vitro</i>, vemurafenib was efficiently transported by both human ABCB1 and
ABCG2, and very efficiently by mouse Abcg2, but not by mouse Abcc2.
Upon oral administration of vemurafenib (5 mg/kg), <i>Abcb1a/1b</i><sup><i>â/â</i></sup> mice had a 1.6-fold
increased, <i>Abcg2</i><sup><i>â/â</i></sup> mice a 2.3-fold increased, and <i>Abcb1a/1b</i><sup><i>â/â</i></sup><i>;Abcg2</i><sup><i>â/â</i></sup> mice a 6.6-fold increased
plasma AUC, respectively, compared to wild-type (WT) mice, indicating
a marked and additive role of these transporters in limiting vemurafenib
oral availability. Brain-to-plasma ratios of vemurafenib (oral, 25
mg/kg) were not increased in <i>Abcg2</i><sup><i>â/â</i></sup> mice, only 1.7-fold in <i>Abcb1a/1b</i><sup><i>â/â</i></sup> mice, but 21.4-fold in <i>Abcb1a/1b</i><sup><i>â/â</i></sup><i>;Abcg2</i><sup><i>â/â</i></sup> mice, indicating pronounced
overlapping functions of these transporters in reducing vemurafenib
brain accumulation. Oral coadministration of the dual ABCB1 and ABCG2
inhibitor elacridar almost completely eliminated the roles of Abcb1
and Abcg2 in restricting oral availability and brain accumulation
of vemurafenib. As predicted by previously described pharmacokinetic
modeling, halving the amount of active efflux transport at the WT
bloodâbrain barrier by testing heterozygous <i>Abcb1a/1b</i><sup><i>+/â</i></sup><i>;Abcg2</i><sup><i>+/â</i></sup> mice had little impact on vemurafenib
brain accumulation. Our data suggest that elacridar coadministration
may be considered to improve the therapeutic efficacy of vemurafenib,
especially for brain metastases located behind a functional bloodâbrain
barrier
Brain Accumulation of Ponatinib and Its Active Metabolite, <i>N</i>âDesmethyl Ponatinib, Is Limited by PâGlycoprotein (P-GP/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2)
Ponatinib is an oral BCR-ABL1 inhibitor
for treatment of advanced
leukemic diseases that carry the Philadelphia chromosome, specifically
containing the T315I mutation yielding resistance to previously approved
BCR-ABL1 inhibitors. Using <i>in vitro</i> transport assays
and knockout mouse models, we investigated whether the multidrug efflux
transporters ABCB1 and ABCG2 transport ponatinib and whether they,
or the drug-metabolizing enzyme CYP3A, affect the oral availability
and brain accumulation of ponatinib and its active <i>N</i>-desmethyl metabolite (DMP). <i>In vitro</i>, mouse Abcg2
and human ABCB1 modestly transported ponatinib. In mice, both Abcb1
and Abcg2 markedly restricted brain accumulation of ponatinib and
DMP, but not ponatinib oral availability. Abcg2 deficiency increased
DMP plasma levels âŒ3-fold. Cyp3a deficiency increased the ponatinib
plasma AUC 1.4-fold. Our results suggest that pharmacological inhibition
of ABCG2 and ABCB1 during ponatinib therapy might benefit patients
with brain (micro)Âmetastases positioned behind an intact blood-brain
barrier, or with substantial expression of these transporters in the
malignant cells. CYP3A inhibitors might increase ponatinib oral availability,
enhancing efficacy but possibly also toxicity of this drug
Preclinical Mouse Models To Study Human OATP1B1- and OATP1B3-Mediated DrugâDrug Interactions <i>in Vivo</i>
The impact of OATP drug uptake transporters
in drugâdrug
interactions (DDIs) is increasingly recognized. OATP1B1 and OATP1B3
are human hepatic uptake transporters that can mediate liver uptake
of a wide variety of drugs. Recently, we generated transgenic mice
with liver-specific expression of human OATP1B1 or OATP1B3 in a mouse
Oatp1a/1b knockout background. Here, we investigated the applicability
of these mice in OATP-mediated drugâdrug interaction studies
using the prototypic OATP inhibitor rifampicin and a good OATP substrate,
the anticancer drug methotrexate (MTX). We next assessed the possibility
of OATP-mediated interactions between telmisartan and MTX, a clinically
relevant drug combination. Using HEK293 cells overexpressing OATP1B1
or OATP1B3, we estimated IC50 values for both rifampicin (0.9 or 0.3
ÎŒM) and telmisartan (6.7 or 7.9 ÎŒM) in inhibiting OATP-mediated
MTX uptake <i>in vitro</i>. Using wild-type, Oatp1a/1bâ/â,
and OATP1B1- or OATP1B3-humanized transgenic mice, we found that rifampicin
inhibits hepatic uptake of MTX mediated by the mouse Oatp1a/1b and
human OATP1B1 and OATP1B3 transporters at clinically relevant concentrations.
This highlights the applicability of these mouse models for DDI studies
and may be exploited in the clinic to reduce the dose and thus methotrexate-mediated
toxicity. On the other hand, telmisartan inhibited only human OATP1B1-mediated
hepatic uptake of MTX at concentrations higher than those used in
the clinic; therefore risks for OATP-mediated clinical DDIs for this
drug combination are likely to be low. Overall, we show here that
OATP1B1- and OATP1B3-humanized mice can be used as <i>in vivo</i> tools to assess and possibly predict clinically relevant DDIs
Organic Anion-Transporting Polypeptides 1a/1b Control the Hepatic Uptake of Pravastatin in Mice
Organic anion-transporting polypeptides (OATPs) mediate
the hepatic
uptake of many drugs. Hepatic uptake is crucial for the therapeutic
effect of pravastatin, a cholesterol-lowering drug and OATP1A/1B substrate.
We aimed to gain empirical insight into the relationship between OATPs
and pravastatin pharmacokinetics and toxicity. We therefore compared
the distribution and toxicity of pravastatin in wild-type and Oatp1a/1b-null
mice. Intestinal absorption of pravastatin was not affected by Oatp1a/1b
absence, but systemic plasma exposure (AUC) increased up to 30-fold
after oral bolus administration. This increased plasma exposure resulted
from reduced hepatic uptake, as evident from 10 to 100-fold lower
liver-to-plasma concentration ratios. However, the reductions in liver
exposure were far smaller (<2-fold) than the increases in plasma
exposure. Reduced pravastatin liver uptake in Oatp1a/1b-null mice
was more obvious shortly after intravenous administration, with 8-fold
lower biliary pravastatin excretion. Although mice chronically exposed
to pravastatin for 60 days evinced little muscular toxicity, Oatp1a/1b-null
mice displayed 10-fold higher plasma concentrations and 8-fold lower
liver concentrations than wild-type mice. Thus, Oatp1a/1b transporters
importantly control the hepatic uptake of pravastatin. Activity-reducing
human OATP1B polymorphisms may therefore both reduce pravastatin therapeutic
efficacy in the liver and increase systemic toxicity risks, thus compromising
its therapeutic index in a two-edged way
Pâglycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain Disposition and Oral Availability of the Novel Taxane Cabazitaxel (Jevtana) in Mice
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)Âmetastases or primary
tumors positioned wholly or partly behind a functional bloodâbrain
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