Biomedical Engineering Reference
In-Depth Information
Modulation of Pgp activity with selective inhibitors could also be a useful strategy
to increase the oral bioavailability of Pgp substrate drugs, in particular to develop
oral formulations of anticancer drugs transported by Pgp. Several in vivo studies in
animals (see above) and clinical trials in humans have been performed to evaluate
the feasibility and the safety of this approach (coadministration of a substrate drug
and a Pgp inhibitor). In a clinical study, cyclosporin A, an effective Pgp blocker,
followed by oral paclitaxel (a well-known Pgp substrate), increased systemic exposure
to paclitaxel eightfold
162
(Figure 24.1
b
). Cyclosporin A also effectively increased the
oral bioavailability of docetaxel from 8% to 91%.
163
Elacridar, an effective inhibitor
of BCRP as well as of Pgp, increased the oral bioavailability of topotecan from 40%
to 97%.
164
These oral strategies turned out to be safe and clinically active.
164
-
166
Modulation of Pgp activity to improve the oral bioavailability of drug substrates is
actually a field of research for HIV protease inhibitors (HPIs), as it has been demon-
strated that almost all of them (in particular, indinavir, saquinavir, nelfinavir, and
ritonavir) are good substrates of Pgp.
97
-
99
,
167
Inhibition of intestinal and possibly
also hepatobiliary Pgp would increase HPI oral bioavailability; retard HPI elimina-
tion, avoiding undertreatment and development of HPI-resistant HIV variants; and
reduce the necessary frequency of drug dosing. This may result in increased com-
pliance of patients to the therapy.
167
The inhibition of Pgp in subclasses of lympho-
cytes might increase the intracellular HPI concentration, thereby enhancing the drug's
effectiveness.
167
In addition, blockade of Pgp in the blood-brain, blood-testis, and
blood-nerve barriers would increase HPI penetration and retention in the putative
pharmacological sanctuaries that are thought to harbor reservoirs of poorly tractable
HIV copies that can reinvade the circulation, thus avoiding eradication of the HIV. In
in vivo experiments, the concentrations of indinavir, nelfinavir, and saquinavir in the
brain were increased significantly in Pgp knockout mice compared with wild-type
mice.
98
,
168
Edwards et al. reported a significantly increased accumulation of ampre-
navir in brain tissue after coadministration of the Pgp/BCRP inhibitor GF120918
(elacridar).
169
Indeed, an interesting clinical application of selective modulation of Pgp activ-
ity might lead to an increase in the passage of certain drugs across the blood-brain
barrier, which might considerably extend the range of drugs available for treatment
of brain disorders.
170
These include primary and metastatic tumors, microbial infec-
tions, HIV infections, mood disorders, and neurological treatment-resistant diseases
(e.g., refractory epilepsy and schizophrenia). Furthermore, preclinical studies have
shown that the brain penetration of anticancer drugs which are transported by Pgp,
such as paclitaxel, docetaxel, and imatinib, can be improved by concomitant use of
Pgp inhibitors, such as cyclosporin A, valspodar, elacridar, and zosuquidar.
171
-
175
A clinical study determining the brain penetration of paclitaxel in combination with
elacridar in patients with primary brain tumors is ongoing, and the preliminary re-
sults are reported to be promising.
176
Similarly, clinical trials are exploring the activity
of imatinib (Gleevec) against central nervous system (CNS) tumor glioblastoma,
177
based on promising preclinical results. However, taking into account that imatinib
is a good Pgp and BCRP substrate drug with limited distribution to the brain,
178
,
179
and that preclinical studies reported that combination of imatinib with an effective
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