of disintegrants on e
intestinal tissues
Werner Gerber, Josias H. Ham
l Scien
ue to inhibition of P-gp
centration dependent
rants to the intestinal
t are susceptible to P-
gp related efflux. However, the clinical significance of these in vitro permeation findings
ed by Elsevier Taiwan
NC-ND license (http://
censes/by-nc-nd/4.0/).
1. Introduction
The oral delivery route is the most preferred route for drug
administration. The safety, ease of administration and flexible
dosage form design include some of the advantages that
contribute to its popularity [1,2]. Essentially, all oral dosage
forms contain excipients, which can be defined as the in-
gredients other than the active pharmaceutical ingredient(s)
that comprise a completed dosage form [3,4]. Disintegrants
are included in some immediate release solid oral dosage
forms (e.g. tablets) to mediate breakup of the drug delivery
* Corresponding author. Fax: þ27 18 299 2248.
Available online at www.sciencedirect.com
ScienceDirect
ww
j o u r n a l o f f o o d and d r u g an a l y s i s x x x ( 2 0 1 8 ) 1e1 0E-mail address: sias.hamman@nwu.ac.za (J.H. Hamman).should be confirmed by means of in vivo studies.
Copyright © 2018, Food and Drug Administration, Taiwan. Publish
LLC. This is an open access article under the CC BY-
creativecommons.org/liP-glycoprotein
Pharmacokinetic interactions
Rhodamine 123
another disintegrant (e.g. sodium alginate) changed R123 transport d
in conjunction with a transient opening of the tight junctions in a con
way. It may be concluded that the co-application of some disinteg
epithelium may lead to pharmacokinetic interactions with drugs thaExcipient
Ex vivo
showed that some of the selected disintegrants (e.g. Ac-di-sol and Kollidon CL-M)
increased R123 absorptive transport due to inhibition of P-gp related efflux, whileCentre of Excellence for Pharmaceutica
South Africa
a r t i c l e i n f o
Article history:
Received 29 September 2017
Received in revised form
18 January 2018
Accepted 19 January 2018
Available online xxx
Keywords:
Disintegrantshttps://doi.org/10.1016/j.jfda.2018.01.007
1021-9498/Copyright © 2018, Food and Drug Adm
BY-NC-ND license (http://creativecommons.org
Please cite this article in press as: GerberW,
excised pig intestinal tissues, Journal of Foofflux across excised pig
man*, Johan D. Steyn
ces, North-West University, Private Bag X6001, Potchefstroom, 2520,
a b s t r a c t
Pharmaceutical excipients were designed originally to be pharmacologically inert. How-
ever, certain excipients were found to have altering effects on drug pharmacodynamics
and/or pharmacokinetics. Pharmacokinetic interactions may be caused by modulation of
efflux transporter proteins, intercellular tight junctions and/or metabolic enzyme amongst
others. In this study, five disintegrants from different chemical classes were evaluated for
P-glycoprotein (P-gp) related inhibition and tight junction modulation effects. Bi-
directional transport studies of the model compound, Rhodamine 123 (R123) were con-
ducted in the absence (control group) and presence (experimental groups) of four con-
centrations of each selected disintegrant across excised pig jejunum tissue. The results
® ®Excipient-drug ph acokinetic interactions: EffectarmOriginal Articlejournal homepage:inistration, Taiwan. Publis
/licenses/by-nc-nd/4.0/).
et al., Excipient-drug pha
d and Drug Analysis (201w.j fda-onl ine.comhed by Elsevier Taiwan LLC. This is an open access article under the CC
rmacokinetic interactions: Effect of disintegrants on efflux across
8), https://doi.org/10.1016/j.jfda.2018.01.007
Efflux transport by members of the ATP-binding cassette
j o u r n a l o f f o o d and d ru g an a l y s i s x x x ( 2 0 1 8 ) 1e1 02(ABC) transporter proteins is responsible for decreasing ab-
sorption of substrates from the gastro-intestinal tract after
oral administration by actively transporting the molecules
back into the lumen from the epithelial cells. This active efflux
transport may result in a reduced bioavailability of orally
administered drugs that are substrates of these efflux proteins
[10,11]. Intentional or unintentional inhibition of P-gp related
efflux of a drug in the epithelium of the gastro-intestinal tract
would result in the increased uptake of a drug that is a sub-
strate of this efflux transporter when co-administered with
the efflux inhibitor [12]. Certain pharmaceutical excipients
have shown the ability to inhibit P-gp related efflux and/or
modulate tight junctions and thereby enhance the absorption
of certain drugs across the intestinal epithelium as well as
change the in vivo pharmacokinetic profiles of some drugs
[6,7,13,14].
R123 is a known P-gp substrate that has been used as
model compound in previous studies to investigate the
modulating effect of selected chemicals (e.g. Brijs) on
absorptive and secretory transport across Caco-2 cell mono-
layers as well as intestinal absorption in rats [2]. R123 has also
been used as a representative P-gp substrate in an in situ
closed loop study in rats to investigate the effect of sodium
nitroprusside on absorption and excretion in the ileum [15].
2. Materials and methods
2.1. Materials
R123, KrebseRinger bicarbonate (KRB) buffer and sodium
alginate (batch number MKBN7680V) were purchased from
SigmaeAldrich (Johannesburg, South Africa). Cro-
scarmellose sodium (Ac-di-sol®, batch number T017C) and
microcrystalline cellulose (Avicel® PH-200, batch number
M939C) were purchased from FMC Corporation (Cork,
Ireland). Sodium starch glycolate (Explotab®, batch number
SSGP0601) was purchased from Mirren (PTY) LTD and cro-
spovidone (Kollidon® CL-M, batch number 91416136W0) was
purchased from BASF (Ludwigshafen, Germany). Costar® 96-
well plates (lot number 07914036) were purchased from Thesystem into smaller units, which leads to a larger surface area
with increased dissolution, absorption and bioavailability
[5,6]. Although most pharmaceutical excipients in solid oral
dosage forms have been considered inert, it has been observed
that certain excipients can increase membrane permeability
of drug molecules or decrease absorption by means of
different mechanisms [6,7].
Pharmacokinetic interactions occur when one compound
alters the pharmacokinetics (i.e. the absorption, distribution,
metabolism and/or excretion) of another compound [8].
Pharmacokinetic interactions may be caused by different
mechanisms of action. It has, for example, been demonstrated
that metabolic enzymes such as cytochrome P450 as well as
active efflux transporters such as P-gp can be modulated (i.e.
inhibition, induction or activation) by certain compounds to
alter the pharmacokinetics of co-administered drugs [6,7,9].Scientific Group (Randburg, South Africa). Pig intestinal tis-
sue was collected at a local abattoir in Potchefstroom, South
Please cite this article in press as: Gerber W, et al., Excipient-drug pha
excised pig intestinal tissues, Journal of Food and Drug Analysis (2013. Bi-directional transport studies
3.1. Preparation of solutions
All the selected disintegrants were evaluated for transport
effects at four different concentrations based on the recom-
mended minimum and maximum quantities to be incorpo-
rated into tablet formulations [16e20] as well as taking into
account that a tablet (e.g. 200 mg as a typical example) is
commonly takenwith 100ml (scenario 1) to 200ml (scenario 2)
of fluid [7]. The mass of each selected disintegrant that was
used to prepare 50 ml of each test solution/suspension for the
transport studies are given in Table 1.
R123 was used as model compound and was completely
dissolved in KRB to a final concentration of 5 mM in the bi-
directional transport studies, since it is a fluorescence
marker that is also a substrate of the P-gp efflux transporter
[2,15,21,22]. For the transport experiments in the apical-to-
basolateral (absorptive) direction, the R123 and required
amount of disintegrant was mixed and placed in the apical
chamber, while KRB was placed in the basolateral chamber.
For the transport studies in the basolateral-to-apical (secre-
tory) direction, two separate solutions were applied to the
different half cells of each diffusion chamber. A clear solution
of R123 (5 mM) in KRB buffer was inserted in the basolateral
side, while a solution/suspension of each disintegrant in KRB
buffer was placed in the apical side.
The rationale behind the application of two different so-Africa. The chemical structures of the selected disintegrants
are shown in Fig. 1.
2.2. Preparation of pig intestinal tissue for ex vivo
transport studies
Before every transport experiment, a piece of approximately
20 cm of pig proximal jejunum was collected from an abattoir
(Potchefstroom, South Africa) directly after slaughter of the
animal. Jejunum tissue was obtained from Landrace pigs,
which forms part of the domestic pig family (Sus scrofa
domesticus), that are bred on farms in South African and
routinely slaughtered for meat production. All animals used
were designated for slaughter by the abattoir on behalf of in-
dependent providers. Feeder pigs ranging from approximately
4 to 6monthswere selected as far as possible for tissue sample
collection. After excision of this intestinal segment, it was
rinsed and submerged in freshly prepared, ice-cold KRB
buffer. On arrival at the laboratory, the intestinal segmentwas
pulled over a glass tube and the serosal layer was stripped off
via blunt dissection. The jejunum tissue was cut along the
mesenteric border and the resulting sheet of tissue was
spread open onto filter paper. The intestinal tissue sheet was
cut into smaller segments, which were mounted between the
half-cells of six Sweetana-Grass diffusion chambers. Peyer's
patches were avoided when selecting jejunal tissue pieces
suitable for mounting between the half-cells of the diffusion
apparatus [1,14].lutions to the chambers for the transport studies in the
basolateral-to-apical direction as described above, was to
rmacokinetic interactions: Effect of disintegrants on efflux across
8), https://doi.org/10.1016/j.jfda.2018.01.007
j o u r n a l o f f o o d and d r u g an a l y s i s x x x ( 2 0 1 8 ) 1e1 0 3ensure that the disintegrants were always exposed to the
apical side of the excised tissue to simulate normal conditions
as it would occur in vivo. Most disintegrants are not absorbed
into the systemic circulation from the gastro-intestinal tract
due to their large molecular weight and poor water solubility
characteristics.
Fig. 1 e Chemical structures of the selected disintegrants: A) Ac
and E) sodium alginate.
Table 1 e The recommended minimum (Min) and maximum (
formulations and the mass of each disintegrant per 50 ml volu
Disintegrant Recommended c
Ac-di-sol® (ADS) (Croscarmellose sodium) Min
Max
Avicel® PH-200 (AVC) (Microcrystalline cellulose) Min
Max
Explotab® (XPT) (Sodium starch glycolate) Min
Max
Kollidon® CL-M (KLM) (Crospovidone) Min
Max
Sodium alginate (SAL) Min
Max
Please cite this article in press as: GerberW, et al., Excipient-drug pha
excised pig intestinal tissues, Journal of Food and Drug Analysis (2013.2. Transport studies
The chambers (assembled half-cells) of the Sweetana-Grass
diffusion apparatus were connected to a heating block
(37 C) and carbogen (95% O2:5% CO2) was bubbled through the
buffer in each half-cell. Thereafter, pre-heated (37 C) KRB
-di-sol®, B) Explotab®, C) Avicel® PH-200, D) Kollidon® CL-M
Max) quantities of each selected disintegrant for tablet
me of each test solution prepared for the transport studies.
oncentration (% w/w) in tablet Mass (mg)
Scenario 1 Scenario 2
0.50 0.50 0.25
5.00 5.00 2.50
5.00 5.00 2.50
15.00 15.00 7.50
2.00 2.00 1.00
8.00 8.00 4.00
2.00 2.00 1.00
5.00 5.00 2.50
2.50 2.50 1.25
10.00 10.00 5.00
rmacokinetic interactions: Effect of disintegrants on efflux across
8), https://doi.org/10.1016/j.jfda.2018.01.007
app
calculate the efflux ratio (ER) of R123 in the presence and
values in the absorptive and secretory directions as well as ER
j o u r n a l o f f o o d and d ru g an a l y s i s x x x ( 2 0 1 8 ) 1e1 04absence of the selected disintegrants (Equation (3)) [2,14].
ER ¼ Papp ðBAÞ
Papp ðA BÞ (3)
where Papp (B-A) is the permeability coefficient for permeation
in the basolateral to the apical direction and Papp (A-B) the
same variable in the apical to basolateral direction.
Analysis of variance (ANOVA) was performed on all data
gathered to determine if there were any statistically sig-
nificant differences between the Papp values of the experi-
mental groups when compared to that of the control group
(R123 alone). Post-hoc tests such as the Dunnett's t-test
and the KruskaleWallis test were used to analyze all
non-parametric data to determine if any statistically sig-
nificant differences were evident. When p  0.05, itbuffer was incubated on both sides of the mounted excised
intestinal tissue for 15 min to accustom the excised tissues to
the experimental conditions. The KRB buffer was then aspi-
rated and the test solutions/suspensions were applied as
described above. Samples of 180 ml were collected from the
acceptor side at 20 min intervals for a total of 120 min and
replaced with an equal volume of KRB buffer [14]. All the
transport studies were performed in triplicate.
3.3. Fluorescent spectroscopic analysis
A validated fluorescence spectroscopic method was used to
analyze the transport samples for R123 content on a Spec-
tramax Paradigm® multi-mode detection platform plate
reader. Excitation and emission wavelengths were set to
480 nm and 520 nm respectively [21,22].
3.4. Data analysis
The concentration of R123 in the transport samples were
corrected for dilution and its transport was expressed as a
percentage of the initial concentration of R123 applied to the
donor chamber (Equation (1)). The percentage transport was
plotted as a function of time to produce percentage transport
curves.
% Transport ¼ Concentration at specific time point
Concentration in donor solution
 100 (1)
The apparent permeability coefficient (Papp) values for R123
were calculated from the percentage transport curves in the
absence and presence of the selected disintegrants (Equation
(2)) [2,14,22].
Papp ¼ dQdt
1
A:60:C0

 
(2)
where Papp is the apparent permeability coefficient (cm$s
1), dQdt
is the permeability rate (amount permeated per minute), A is
the diffusion area of the membrane (cm2) and C0 is the initial
concentration of R123 [2,14,22].
The P values in both transport directions were used towas considered to be indicative of statistically significant
differences.
Please cite this article in press as: Gerber W, et al., Excipient-drug pha
excised pig intestinal tissues, Journal of Food and Drug Analysis (2014. Results and discussion
The effects of each selected disintegrant on the transport of
R123 in two directions (i.e. absorptive and secretory) across
excised pig intestinal tissues are reported below.
4.1. Ac-di-sol® (ADS)
The % transport, apparent permeability coefficient (Papp)
values in the absorptive and secretory directions as well as ER
values for R123 across excised pig intestinal tissues in the
absence (control group) and presence of Ac-di-sol® (ADS) at
four concentrations are shown in Fig. 2.
ADS mediated a concentration dependent increase in R123
transport in the absorptive direction across the pig intestinal
tissue. Statistically significant increases in absorptive trans-
port were evident at the two highest concentrations tested
(namely 0.005% and 0.01%w/v) in comparisonwith the control
group of R123 alone (Fig. 2C). ADS also mediated a simulta-
neous, concentration dependent, decrease in secretory R123
transport. However, the lower two concentrations did cause
an increase in secretory transport of R123 as compared to the
control group. This may be explained by a simultaneous
reduction in the trans-epithelial electrical resistance (TEER).
TEER reflects the ionic conductance of the paracellular
pathway in the membrane and may be used to deduce the
extent of paracellular transport. The TEER reduction for the
transport studies in the secretory direction was 42.31%,
55.29%, 21.6% and 54.20%, respectively for each concentration
tested. The decrease in TEER is indicative of a partial opening
of the intercellular tight junctions. It has previously been re-
ported in the literature that R123 is capable of being trans-
ported via the paracellular route [15]. Therefore, it can be
concluded that the increased secretory transport of R123 in
the presence of ADS at 0.0005% (w/v) and 0.001% (w/v) may be
attributed to the contribution of the increased transport via
the paracellular route. On the other hand, the statistically
significant reduction in the secretory transport of R123 at the
highest concentration of ADS may be explained by the over-
whelming inhibition effect on P-gp related efflux, which
makes the contribution of paracellular transport negligible.
The efflux ratio (ER) values (Fig. 2D) may be used to identify
the main transport modulation mechanism of the co-applied
disintegrant. When ER >> 1, it indicates that a compound is
susceptible to active efflux transport, while an ER << 1 is
indicative of active absorptive uptake while an ER value equal
or close to 1 indicates that passive diffusion is the main
transport mechanism of the compound [23]. Fig. 2D shows
that R123 in the control group was actively transported via an
efflux based mechanism with a corresponding ER value of
2.20. A concentration dependent ER reduction was observed
when ADS was co-applied with R123, which indicated a con-
centration dependent inhibition of P-gp related efflux.
4.2. Avicel® PH-200 (AVC)
The % transport, apparent permeability coefficient (Papp)values for R123 across excised pig intestinal tissues in the
rmacokinetic interactions: Effect of disintegrants on efflux across
8), https://doi.org/10.1016/j.jfda.2018.01.007
j o u r n a l o f f o o d and d r u g an a l y s i s x x x ( 2 0 1 8 ) 1e1 0 5absence (control group) and presence of Avicel® PH-200 (AVC)
at four concentrations are shown in Fig. 3.
When considering the results of the secretory transport
(Fig. 3B) of R123 in the presence of AVC, it appears that P-gp
related efflux was inhibited in a concentration dependent
manner. The results also showed a general improvement of
R123 transport in the absorptive direction in the presence of
AVC, but this transport enhancement is accompanied with a
concentration dependent decrease (Fig. 3A). Statistical anal-
ysis of the data showed that AVC at the lowest concentration
(0.005% w/v) yielded a statistically significant increase in the
transport of R123 in the absorptive direction, while also
decreasing the transport of R123 in the secretory direction (i.e.
an efflux inhibition with an ER value of 0.90) (Fig. 3C and D).
Fig. 2 e Graphical presentation of the percentage transport of R
directions (C) apparent permeability coefficient (Papp) values for b
the presence of Ac-di-sol® (ADS) at four concentrations across e
significant differences from the control, p ≤ 0.05).
Please cite this article in press as: GerberW, et al., Excipient-drug pha
excised pig intestinal tissues, Journal of Food and Drug Analysis (201A probable explanation for the concentration dependent
decrease in R123 transport in the absorptive direction may be
due to physical or chemical interactions between R123 mole-
cules and AVC particles (e.g. the formation of complexes or
adsorption onto the surface of particles). The results suggest
that the extent of the complex formation was concentration
dependent and that complexes only formed above a certain
AVC concentration, which would explain the increase in R123
transport at the lower two concentrations, but not at the two
higher concentrations. These findings are in accordance with
the results from a similar study [2], where a reduction in R123
transport across rat intestinal tissue was reported in the
presence of certain surfactants at concentrations higher than
the criticalmicelle concentration. In addition to the above, it is
hodamine 123 in the (A) absorptive and (B) secretory
i-directional transport and (D) the efflux ratio (ER) values in
xcised pig intestinal tissues (* indicates statistically
rmacokinetic interactions: Effect of disintegrants on efflux across
8), https://doi.org/10.1016/j.jfda.2018.01.007
j o u r n a l o f f o o d and d ru g an a l y s i s x x x ( 2 0 1 8 ) 1e1 06known that AVC is poorly water soluble [18] and forms sus-
pensions in aqueous media of which the particles may
aggregate. It is possible that when AVC particles aggregate
together to form clumps, that some R123 molecules can get
trapped within these structures.
4.3. Explotab® (XPT)
The % transport, apparent permeability coefficient (Papp)
values in the absorptive and secretory directions as well as ER
values for R123 across excised pig intestinal tissues in the
absence (control group) and presence of Explotab® (XPT) at
four concentrations are shown in Fig. 4.
R123 transport in both directions was limited to relatively
low Papp values (i.e. below about 2.40  107 cm.s1) for all XPT
concentrations that were co-applied (Fig. 4C). Although the P-
Fig. 3 e Graphical presentation of the percentage transport of R
directions (C) apparent permeability coefficient (Papp) values for b
the presence of Avicel® PH-200 (AVC) at four concentrations acr
significant differences from the control, p ≤ 0.05).
Please cite this article in press as: Gerber W, et al., Excipient-drug pha
excised pig intestinal tissues, Journal of Food and Drug Analysis (201gp related efflux (i.e. transport in the secretory direction) was
inhibited statistically significantly, the absorptive transport of
R123 was not increased at all. This lack of increase in
absorptive transport can possibly be explained by the exper-
imental setup where XPT was applied in the apical chamber
together with the R123 for the absorptive transport experi-
ment. According to the literature [17], XPT is virtually insol-
uble in water and has the ability to swell to approximately 300
times its initial size. The swollen XPT particles may have
formed a hydrated layer with increased viscosity on the tissue
surfaces, which mediated a reduction in the diffusion rate
according to Fick's law of diffusion for the absorptive trans-
port studies. Physical or chemical interactions between R123
molecules and XPT particlesmay also have contributed to this
effect. Since the R123 was applied alone to the basolateral side
for the secretory transport experiments, these effects did not
hodamine 123 in the (A) absorptive and (B) secretory
i-directional transport and (D) the efflux ratio (ER) values in
oss excised pig intestinal tissues (* indicates statistically
rmacokinetic interactions: Effect of disintegrants on efflux across
8), https://doi.org/10.1016/j.jfda.2018.01.007
j o u r n a l o f f o o d and d r u g an a l y s i s x x x ( 2 0 1 8 ) 1e1 0 7occur in the secretory transport direction where R123 was
applied to the basolateral side. Inhibition of P-gp transporters
by the XPT applied to the apical side decreased the secretory
transport of R123, but it did not result in an increased
absorptive transport due to the reasons described above.
4.4. Kollidon® CL-M (KLM)
The % transport, apparent permeability coefficient (Papp)
values in the absorptive and secretory directions as well as ER
values for R123 across excised pig intestinal tissues in the
absence (control group) and presence of Kollidon® CL-M (KLM)
at four concentrations are shown in Fig. 5.
Fig. 4 e Graphical presentation of the percentage transport of R
directions (C) apparent permeability coefficient (Papp) values for b
the presence of Explotab® (XPT) at four concentrations across e
significant differences from the control, p ≤ 0.05).
Please cite this article in press as: GerberW, et al., Excipient-drug pha
excised pig intestinal tissues, Journal of Food and Drug Analysis (201From Fig. 5 it is clear that KLM inhibited P-gp related efflux
transport of R123 in the secretory direction in a concentration
dependent manner (Fig. 5B), which resulted in a correspond-
ing concentration dependent increase in R123 absorptive
transport (Fig. 5A). At the highest KLM concentration tested
(i.e. 0.01% w/v) statistically significant enhancement of
absorptive transport was found to be as much as 3 fold higher
than that of the control group (Fig. 5C). In the secretory di-
rection it is shown that KLM inhibited P-gp to such an extent
that all transport of R123 was statistically significantly lower
than the control group. Furthermore, the reduction in ER
values confirmed an inhibition of P-gp related efflux transport
by KLM (Fig. 5D), especially when taken into consideration
hodamine 123 in the (A) absorptive and (B) secretory
i-directional transport and (D) the efflux ratio (ER) values in
xcised pig intestinal tissues (* indicates statistically
rmacokinetic interactions: Effect of disintegrants on efflux across
8), https://doi.org/10.1016/j.jfda.2018.01.007
j o u r n a l o f f o o d and d ru g an a l y s i s x x x ( 2 0 1 8 ) 1e1 08that the TEER measurements had shown that no effects were
elicited on tight junctions and paracellular transport (results
not shown).
4.5. Sodium alginate (SAL)
The % transport, apparent permeability coefficient (Papp)
values in the absorptive and secretory directions as well as ER
values for R123 across excised pig intestinal tissues in the
absence (control group) and presence of sodium alginate at
four concentrations are shown in Fig. 6.
The lower three concentrations (0.0025%, 0.005% w/v and
0.01% w/v) of SAL caused an increase in R123 absorptive
Fig. 5 e Graphical presentation of the percentage transport of R
directions (C) apparent permeability coefficient (Papp) values for b
the presence of Kollidon® CL-M (KLM) at four concentrations ac
significant differences from the control, p ≤ 0.05).
Please cite this article in press as: Gerber W, et al., Excipient-drug pha
excised pig intestinal tissues, Journal of Food and Drug Analysis (201transport, while the highest concentration caused a decrease
in R123 absorptive transport when compared to the control
(Fig. 6A). In the secretory direction, however, all the Papp
values for R123 were statistically significantly lower than that
of the control group. A gradual apparent increase in the Papp
values for R123 transport in the secretory direction was
evident as the SAL concentration increased (Fig. 6B).
To explain these permeability results, it is necessary to take
the TEER values into consideration. During the transport
studies in the absorptive direction, the TEER value decreased
by approximately 18% at the lowest concentration of SAL,
while the TEER increased by 5% at the highest SAL concen-
tration. A similar result was found with TEER values in the
hodamine 123 in the (A) absorptive and (B) secretory
i-directional transport and (D) the efflux ratio (ER) values in
ross excised pig intestinal tissues (* indicates statistically
rmacokinetic interactions: Effect of disintegrants on efflux across
8), https://doi.org/10.1016/j.jfda.2018.01.007
j o u r n a l o f f o o d and d r u g an a l y s i s x x x ( 2 0 1 8 ) 1e1 0 9secretory direction where a 41% decrease in TEER was caused
by SAL at the lowest concentration and a 31% increase in TEER
was observed for the highest concentration. These results
indicate that tight junctions were modulated to open up at the
lower concentrations, but tightened at the higher concentra-
tions of SAL. It therefore seemed that both efflux inhibition and
tight junction opening played a role in R123 transport at lower
concentrations of co-applied SAL, while only efflux inhibition
played a role at higher concentrations of co-applied SAL.
5. Conclusions
Based on the in vitro permeation results from this study it is
clear that certain excipients may alter drug absorption via
various mechanisms such as alterations in P-gp related
Fig. 6 e Graphical presentation of the percentage transport of R
directions (C) apparent permeability coefficient (Papp) values for b
the presence of sodium alginate (SAL) at four concentrations ac
significant differences from the control, p ≤ 0.05).
Please cite this article in press as: GerberW, et al., Excipient-drug pha
excised pig intestinal tissues, Journal of Food and Drug Analysis (201efflux, tight junction modulation or by interactions with the
drugmolecules. Ac-di-sol® showed a tendency to inhibit P-gp
related efflux and simultaneously increased paracellular
transport by means of modulating tight junctions. The re-
sults showed that Avicel® PH-200 has an inhibitory effect on
P-gp related efflux, but a complex interaction was probably
involved to reduce the absorptive transport of R123 in a
concentration dependent manner even though a relatively
high increase in absorptive transport was observed at its
lowest concentration tested. Although Explotab® seemed to
inhibit P-gp related efflux; it did not increase absorptive
transport of R123 possibly due to other interactions. Kolli-
don® CL-M also inhibited P-gp related efflux, but did not
exhibit noticeable effects on tight junction as revealed by
TEER results. Sodium alginate most likely altered R123
transport by tight junction modulation, which presented
hodamine 123 in the (A) absorptive and (B) secretory
i-directional transport and (D) the efflux ratio (ER) values in
ross excised pig intestinal tissues (* indicates statistically
rmacokinetic interactions: Effect of disintegrants on efflux across
8), https://doi.org/10.1016/j.jfda.2018.01.007
with an apparent increase in R123 efflux transport. These
in vitro permeation studies showed that certain excipients
such as selected disintegrants may have an effect on drug
transport across intestinal epithelia via different mecha-
nisms of action.
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The authors declare that there are no conflicts of interest.
Acknowledgements
This work was carried out with the financial support of the
National Research Foundation of South Africa (Grant no:
103479). Any opinion, findings and conclusions or recom-
mendations expressed in this material are those of the au-
thors and therefore the NRF do not accept any liability with
regard thereto.
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