EFFLUX PUMP INHIBITION
As shown in the Figure below
transmucosal transport of the P-gp substrate rhodamine 123 (grey graph) is
strongly improved in the presence of thiolated chitosan. [Werle M., and Hoffer M. (2005). Glutathione
and thiolated chitosan inhibit multidrug resistance P-glycoprotein activity
in excised small intestine. J. Control. Rel., 111, 41-46]. Click on the graph to see the difference. These in vitro results could meanwhile be
confirmed by various in vivo studies with various efflux pump substrates.
Föger et al. [Föger F., Schmitz T.,
and Bernkop-Schnürch A. (2006) In vivo evaluation of polymeric delivery
systems for P-glycoprotein substrates. Biomaterials, 27, 4250-4255] for instance showed that the oral
bioavailability of rhodamine 123 is even 3.0- fold improved when this model
P-gp substrate is embedded in thiolated chitosan minitablets given orally to
rats.
Transepithelial transport of
rhodamine-123 (Rho-123) in the absorptive direction in the absence (grey
graph) and presence (Click on the graph to see the difference;
blue graph) of thiolated chitosan at a concentration of 0.5% (m/v).
Transport data are expressed as percentage of the total dose of Rho-123
(0.001% m/v) applied to the apical side of the mucosa. [Werle M. and Hoffer M . (2005). Glutathione
and thiolated chitosan inhibit multidrug resistance P-glycoprotein activity
in excised small intestine. J. Control. Rel., 111, 41-46]. |
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The postulated mechanism of efflux pump inhibition is based on an interaction of
thiomers with the channel forming transmembrane domain of various efflux
pumps such as P-gp and multidrug resistance proteins (MRPs). P-gp, for
instance, exhibits 12 transmembrane regions forming a channel through which
substrates are transported outside of the cell. Two of these transmembrane
domains – namely 2 and 11 – exhibit on position 137 and 956, respectively, a
cysteine subunit. Thiomers seem to enter in the channel of P-gp and likely
form subsequently one or two disulfide bonds with one or both cysteine
subunits located within the channel. Due to this covalent interaction the
allosteric change of the transporter being essential to move drugs outside
of the cell might be blocked [Gottesman M.M. and Pastan I.
(1988). The multidrug transporter, a double-edged sword. J. Biol. Chem.,
263, 12163-12166]. Click on the
picture to see the postulated mechanism.
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In addition, poly(acrylic
acid)-cysteine conjugate showed to inhibit effectively Mrp2 efflux pump
transporter, improving the permeation of sulforhodamine 101 4.67-fold [Grabovac V., Bernkop-Schnürch A. (2006) Thiolated polymers as effective inhibitors of intestinal Mrp2 effluxpump
transporters, Scientia Pharmaceutica 74, 75].
Transepithelial transport of
sulforhodamine 101 (sRho) in the absorptive direction in the absence (grey
bars) and presence of thiolated poly(-acrylic acid) (PAA) of indicated
molecular mass at a concentration of 0.5% (m/v). Click on the graph to see the difference;
blue bars; [Grabovac V.,
Bernkop-Schnürch A. (2006) Thiolated polymers as effective inhibitors of intestinal Mrp2 efflux pump transporters, Scientia Pharmaceutica 74, 75]. |
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