PHYSIOLOGICAL MODELING OF THE

SMALL INTESTINE IN
DRUG ABSORPTION

K. Sandy Pang
Department of Pharmaceutical Sciences
University of Toronto

ORAL DRUG ABSORPTION

The extent and rate of drug absorption are strongly modulated by the
physicochemical properties of drug and physiology of the gastrointestinal
tract (GIT). Additionally, drug dissolution from its dosage form could
constitute the slowest or rate-determining step in drug absorption [1].
The drug needs to leave the aqueous environment to interact with the
membrane for permeation. Then the drug needs to survive metabolism
and efflux by the intestine, liver and lung, the first-pass organs, before
the drug reaches the systemic circulation [2]. These various events may
lead to significant reduction of the orally administered dose.
The intestine is an important tissue that regulates the extent of ab-
sorption of orally administered drugs, and the intestine, liver and lung
are involved in first-pass removal [3,4]. The intestine is unique in that
it is the anterior, portal tissue that regulates the flow of substrates to
the liver, then the lung. The venous drainage of the intestine consti-
tutes the majority of the blood supply to the liver, accounting for 75%
of total liver blood flow. The drug concentration [5,6] and the intestinal
flow rate [7], factors that alter the rate of drug delivery, affect the de-
gree of saturability of the intestine as well as the liver. For drugs that
are highly cleared by the intestine, the contribution of the liver or lung
to drug metabolism will become reduced. By contrast, drugs that are
poorly extracted by the intestine are able to reach the next first-pass
organs, the liver and the lung, for removal [8,5,9].
This chapter describes the roles of intestinal transporters and metabo-
lism in the determination of oral bioavailability and first-pass removal.
The majority of drug absorption occurs at the small intestine instead of
4

the stomach or the large intestine because of the large surface area due to
the presence of villi and microvilli that increase the surface area many-
fold. Both the duodenum and jejunum possess higher surface areas than
the ileum [10].

PHYSICOCHEMICAL PROPERTIES OF DRUGS

There has been much effort devoted to relate the physicochemical
properties of drug with oral drug absorption . The drug, whether a
weak acid or weak base, the pKa [11–14], the microclimate pH [15],
the unstirred water layer, USWL [16,17], solubility, dose, and fraction
unionized are factors that impact on the fraction of dose absorbed [18–
20]. The concept of an absorption potential has been utilized to describe
drug absorbability based on the partition coefficient. It is generally ac-
cepted that drugs that are unionized or that undergo hydrogen bonding
exhibit a much greater lipophilicity towards membrane permeation than
their ionic counterparts, whereas too many hydrogen donor or acceptor
groups, however, is not good [21]. Lipophilicity is a major determi-
nant for membrane permeation, and the extent of absorption is often
correlated to the partition coefficient, for drugs that enjoy good aque-
ous solubility when the unstirred water layer is not an imposing barrier
[22]. Predictive models based on Lipinski’s Rule of Five [21], the Quan-
titative Structure Bioavailability Relationship (QSBR) [23], or others
QSAR models [24–27] have been developed to predict drug permeation
potentials.

THE INTESTINE
In addition to mediating passive absorption by the villi and microvilli,
the small intestine is endowed with anionic and cationic transporters
[28–35]. These are found within the enterocytes that are located abun-
dantly at the villous tip (Fig. 1). The various apical transporters for the
absorption of organic anions and cations have been reviewed [29,33,32]
(Table 1). The efflux transporters, known collectively as the ABC (ATP
binding cassette proteins), mediate exsorption at both the apical and
basolateral membranes [36–38]. Important examples are the 170 kDa
P-glycoprotein (Pgp, or the multidrug resistance gene product, MDR1)
[39–42] and the multidrug resistance-associated protein 2 (MRP2) [43–
45]. Moreover, the newly characterized breast cancer resistance pro-
tein (BCRP) multidrug transporter confers resistance to mitoxantrone,
 5

topotecan, the anthracyclines, and related drugs in cell lines [46–51].

Drug efflux back to the intestinal lumen effectively reduces drug absorp-
tion as well as the sojourn of drug within the enterocyte [52–54]. Drugs
may also be effluxed into the circulation by MRP3 [55] or the monocar-
boxylic acid transporter 1, Mct1, [56,57] at the basolateral membrane.

Drug metabolizing enzymes such as the cytochromes [58–64] and Phase

II enzymes [65,66] are present within the enterocytes. Needless to say,
the presence of intestinal enzymes reduces drug bioavailability. Many
drugs are substrates of both Pgp and cytochrome P450 3A [67–69]. Ex-
amples of these are verapamil [70,71], vincristine, etoposide, daunoru-
bicin, paclitaxel [72–75,38,76], digoxin [77,78], the HIV protease in-
hibitor indinavir [79–81], cyclosporin [82,53], tacrolimus [83–85], and
sirolimus [86,87]. Both Pgp and CYP3A are under regulation of the
pregnane X-receptor [88], Although the impact of PXR on liver is well
6
 7

recognized [89], less is known regarding the effect of PXR on drug trans-
port and metabolism within the intestine.

HETEROGENEITY OF INTESTINAL
TRANSPORTERS
Analogous to that found for the liver [5,90,91], there exists an increas-
ing body of literature on the heterogeneity of intestinal transporters (Ta-
ble 2). Although the absorption of some drugs - salicylate [22], antipyrine
[92], acetaminophen [93], griseofulvin [94], (-)-carbovir [154], and meto-
prolol [155] - was similar among all the intestinal segments, variations
in absorption were found for other drugs among the segmental regions.
The extents of absorption of ranitidine [95] and talinolol [96] were higher
in the proximal intestine. Preferential absorption in segmental regions
was noted for the intestinal absorption of ranitidine [156] and diltiazem
[97]. For hydrochlorothiazide, atenolol, furosemide and cimetidine [98],
the net mucosal to serosal absorption was greater for the jejunum than
for the ileum. For verapamil [99], phenytoin, almokalant, gemifibrozil,
metoprolol, omeprazol, propranolol, foscarnet, erythritol, dDVAP [22],
and etoposide [100], net mucosal to serosal absorption was greater for
the ileum over the jejunum.
Recent advances on the detection of immunoreactive proteins have
provided further definitive proof on variations in segmental distributions
of the intestinal transporters [28,101,45,55,102]. The studies revealed
heterogeneity of apical absorptive and secretory transporters among seg-
ments. The faster absorption rate constant of benzoic acid for jejunal
administration in the perfused rat small intestine preparation correlated
well with the higher distribution of the Mct1 (the monocarboxylic acid
transporter 1) among jejunal enterocytes in comparison to those in duo-
denal or ileal segment [103] (Fig. 2). The proton-coupled oligopeptide
transporter 1, Pept1, of the rabbit was more abundant in the proximal
intestine (duodenum and jejunum) [28]; the rat organic anion transporter
3, Oatp3, is higher in the jejunum [55]; the apical bile salt transporter
(Abst) predominates in the distal ileum of the hamster and rat [104,101].
Gotoh et al. [44] demonstrated the greater mRNA expression of Mrp2 in
the rat jejunum, followed by the duodenum and ileum, with very little in
the colon. The same was found by Mottino et al. [45]. The excretion of
the glutathione conjugate 2,4-dinitrophenyl-S-glutathione by Mrp2 was
greatest in the jejunum [44]. By contrast, the Pgp efflux pump is higher
distally at the jejunum and ileum [39,99,105,53,106,74,107,81] (Fig. 2).
The rat basolateral Mrp3 that transports drug out of the cell is highest
8

towards the distal ileum and colon [108]. The heterogeneity of trans-
porters among the intestinal segments (Table 2) is expected to affect
drug absorption and bioavailability.

HETEROGENEITY OF INTESTINAL ENZYMES

FOR METABOLISM
The intestinal tissue is endowed with phase I and II enzymes, usually
at lower levels compared to those for the liver. Drug metabolizing en-
zymes: UDP-glucuronosyltransferases (UGT), sulfotransferases (PST),
and glutathione S-transferases (GST) exhibit a decreasing gradient along
the intestinal wall, from duodenum to ileum [109–111,59] (Table 2). The
distribution of the human intestinal CYP3A4 paralleled that of the rat
for the small intestine, and showed a slightly lower level at the duodenum
before levels rise again at the jejunum, then finally decreasing towards
the ileum [62,64,58,81].
 9

ROUTE-DEPENDENT INTESTINAL
METABOLISM/EXCRETION
The phenomenon of route-dependent intestinal metabolism or excre-
tion has been observed (Table 3). Route-dependent intestinal removal
describes a greater intestinal metabolism/excretion of drug upon oral or
luminal dosing vs. systemic dosing. In studies pertaining to the per-
fused, rat small intestine preparations, greater extents of metabolism
were noted for acetaminophen [157], enalapril [158] morphine [112] and
(-)aminocarbovir, the prodrug that was converted to (-)carbovir [113],
when these were given luminally, whereas metabolism was either absent
or negligible when the drug dose was given into the reservoir for systemic
delivery. The results from the perfused vascular intestinal preparations
mirrored the observations on midazolam hydroxylation in humans. The
drug exhibited a low intestinal extraction ratio (0.09) in anhepatic pa-
tients undergoing liver transplantation with systemic administration,
but extensive first-pass metabolism was noted orally (extraction ratio
of 0.43), with much of the intestinally formed primary metabolite, 1’-
10

hydroxymidazolam, being detected in the hepatic portal blood [62–64].

Also, the erythromycin breath test given intravenously only correlated
to liver but not intestinal CYP3A4 levels [114,115], and the observation
translates to inaccessibility of systemically administered erythromycin to
the intestinal mucosal (CYP3A4) enzymes. Analogously, pre-treatment
of humans with rifampin, a PXR ligand, on Pgp secretion exerted an ef-
fect only on the oral but not intravenous kinetics of digoxin [78], suggest-
ing that the intestinal Pgp is accessible for digoxin administered into the
lumen. The above findings infer the enzymes for preabsorptive intesti-
nal metabolism/efflux are always present in enterocytes facing the lumen
and are unavailable to drugs in the circulation. These observations are
consequences of route-dependent intestinal metabolism/excretion [116].

GASTROINTESTINAL MOTILITY
The presence of interacting drugs and food affects the transit times
within the gastrointestinal tract [117,118]. Variations in gastric emp-
tying rate bring about modulations of intestinal drug absorption. In-
evitably, a delay in stomach emptying reduces the rate of drug absorp-
tion since the delivery rate to the small intestine is prolonged. Acid labile
drugs will endure a greater degradation upon prolongation of stay in the
stomach, thereby diminishing the extent of absorption [119,120]. How-
ever, increasing the sojourn of compounds in the stomach will promote
dissolution and improve the extent of absorption of relatively insoluble
drugs such as griseofulvin and phenytoin [121,122]. But no change is
anticipated for drugs of good water and lipid solubility [119,123]. For
drugs whose intestinal transport is dependent on apical transporters, the
reduced and intermittent release of drug from the stomach to the small
 11

intestine is expected to bring about a desaturation of the transporter

system, rendering increased extents of absorption [124].

INTESTINAL MODELING IN VITRO AND IN

SMALL INTESTINE
Intestinal secretion is often studied in the Caco-2 cell culture system,
where drug may be applied to the apical side (ap) or basolateral (baso)
side (Fig. 3). A greater apical to basolateral flux (A to B) over that
of B to A suggests involvement of Pgp [70]. Upon addition of CYP3A4
to the system, the dynamic interactions of metabolism and secretion
may be estimated. Recent in vitro studies have led to the conclusion
that intestinal metabolism could be enhanced when the substrate is se-
creted by P-glycoprotein due to an increase in the mean residence time
(MRT) of drug in the intestine [125,126]. Theoretical examinations of
the Caco2 cell culture system did support the notion that the MRT
was increased with secretion, but drug metabolism was in fact decreased
with secretion under linear conditions (Fig. 4) [127]. Under nonlinear
metabolism, however, instances existed whereby the metabolite forma-
tion rate may increase even though the ultimate amount of metabolite
formed remained equal to the dose [127]. Increased secretion and rapid
re-absorption of drug from the apical compartment to the cell evoked
desaturation of intestinal enzymes and promoted greater rates of drug
metabolism.
The modeling of drug absorption data in the intact small intestine is
complex, but is often handled simplistically with compartment analy-
ses for first order or zero order absorption [128,129]. Modeling efforts of
data in vivo included the gastrointestinal absorption (GITA) and kinetic
(GITK) models that examine absorption of drug from the stomach, duo-
denum, upper and lower jejunum and ileum, cecum and large intestine
with varying transit times and absorption [118]. The important task re-
mains to provide mechanistically-based modeling so as to allow insight
into intestinal metabolism, efflux, absorption, and intestinal transit, in-
cluding route-dependent intestinal metabolism. There had been the-
oretical investigations on the Compartmental Absorption and Transit
model (CAT) that considered the transit and absorption of drug in the
small intestine (7 compartments) and there was no absorption within the
stomach and colon compartments. Absorption within the seven mixing-
tanks in series compartments for the small intestine was governed by the
gastric emptying rate and different intestinal transit times [130,131,20].
Since the CAT model did not include the physical modeling of drug
12
 13

dissolution from dosage solid forms or controlled release formulations,

degradation in lumen, changes in absorptive surface area, absorption in
the stomach and colon, metabolism in liver, and transporter densities
for absorption and efflux, a refined and expanded model, known as the
Advanced CAT or ACAT model was developed, with implementation
in software, for the prediction of drug absorption [132]. Details such as
particle size, pH, particle density, and diffusion coefficient were included
for consideration of drug dissolution and absorption. In another model,
Ito et al. [133] described intestinal metabolism and secretion, intracel-
lular drug diffusion and permeation through the basolateral membrane;
however, the model seemed to lack description of intestinal flow. More-
over, these models do not relate to drug partitioning, transporters, and
the phenomenon of route-dependent intestinal metabolism. A greater
understanding of the interplay will allow sound interpretations on in-
testinal drug metabolism and transport with respect to other drugs or
the intake of fruit juices [134–136].

Physiological models: Traditional model (TM) and

Segregated Flow Model (SFM)
Experiments based on the perfused rat small intestine preparation had
provided data that led to the understanding of intestinal processes in ab-
sence of the contribution from other eliminating organs. From modeling
of these data with physiologically-based models, the developed models
may be refined and extended to encompass important variables such
as gastrointestinal transit, metabolism, transport, and efflux [112,137]
(Fig. 5). The Traditional physiological Model (TM) (Fig. 5A) was de-
veloped to describe data arising from recirculation of tracer morphine in
the perfused rat small intestine preparation [112]. In this preparation,
morphine glucuronidation was observed with dosing of morphine into
the duodenal lumen and not with administration into the reservoir that
mimicked intravenous administration (Figs. 6 and 7).
To addresses the apparent inaccessibility of intestinal enzymes to the
drug in circulation, the Segregated Flow Model (SFM) was developed
within our laboratory (Fig. 5B). This model was based on modifications
of the model of Klippert and Noordhoek [138]. The SFM described a
small and low portion of the intestinal blood flow to the active enterocyte
region where the absorptive and exsorptive carriers and metabolic en-
zymes reside. The remaining, bulk intestinal blood flow perfuses the non-
absorptive and non-metabolizing regions of the small intestine. These
regions include the serosa, submucosa, and mucosa, excluding the ente-
rocyte region [139]. Thus, the SFM model recognizes the subtle demar-
14

cation of tissue layers and distributions in blood supply [140,141]. The

literature values for the blood flow to the absorptive enterocyte layer of
the mucosa vary greatly, ranging from 5% to 30% [142,143,141]. For the
SFM, drug in the lumen must necessarily enter via the enterocyte region
before reaching the circulation, whereas drug in circulation is primarily
channelled to other non-metabolizing, tissular regions. The consequence
is the greater intestinal metabolism for oral over intravenous dosing, even
when the small intestine is the only removal organ. The properties of
 15

the models were compared; the predicted trends were generally similar
for both TM and SFM, although the magnitudes differed since the flow
to the enterocyte region differed. But the SFM was found superior over
the TM in describing route-dependent intestinal metabolism of tracer
morphine glucuronidation in the vascularly perfused rat small intestine
(Figs. 6 and 7) [139].
These physiologically-based models developed for the intestine (TM
and SFM) also provided the theoretical examination of extents of metabo-
lism and mean residence time (MRT). Under linear conditions, intestinal
secretion resulted in reduced intestinal metabolite formation, as con-
firmed in a recent simulation with the TM and SFM [137]. Both secre-
tion and metabolism reduced biovailability, F, whereas increasing the
absorption rate constant, ka, increased F. The MRT was prolonged in
absence of gastrointestinal transit or luminal metabolism (the kg com-
ponent in Fig. 5), and clearance by other parallel eliminating organs,
denoted as CLo, was unimportant (Table 4). With loss of drug from
lumen (kg component > 0), the MRT was reduced. The conclusions
agree with intuitive and deductive reasoning since reduction of intracel-
lular substrate concentration in the intestine accompanies drug efflux
16

at the apical membrane, yielding lower rates of intestinal metabolism

[144,145]. Increased absorption neutralizes the effect of intestinal secre-
tion and increased F, whereas increased secretion and metabolism reduce
the bioavailability, F [137].

Segmental Traditional Model (STM) and Segmental

Segregated Flow Model (SSFM)
In order to accommodate the attendant heterogeneities of metabolic
and transporter activities and to examine their impact on intestinal
clearance and availability, more advanced models have been developed
[146]. The intestinal compartments of the TM or SFM were expanded
into three equal segmental compartments, analogous to the zonal mod-
eling of the liver [91], in the development of the Segmental, Traditional
Model (STM, Fig. 8A) and the Segmental, Segregated Flow Model
(SSFM, Fig. 8B) [146]. Varying distributions of absorptive and secretory
transporters and metabolic enzymes were expected to result in different
F’s. Through simulations with the STM and SSFM, the highest and
lowest values of F were found within sets of absorptive, metabolism and
 17

secretory activities that were distributed heterogeneously in segments of

the small intestine (Fig. 9). The predicted trends were generally similar
for both STM and SSFM, although the magnitudes differed since the
flow to the enterocyte region differed. Of note is the strong influence of
the distribution of the metabolic enzymes along the intestinal length on
F.
In other simulations of the STM and SSFM based on equal activ-
ities for transport and metabolism among the segments, fast absorp-
tion was found to counteract the effect of the virtual, peripheral com-
 18

partment. This reduced the MRT of drug in intestinal tissue,

[146]. Increases in the metabolic intrinsic clearance within the segments
as well as gastrointestinal transit/clearance de-
creased the MRT whereas a greater secretory intrinsic clearance
followed by reabsorption increased the Rapid absorption
of the secreted species cancelled the effect of intestinal secretion and in-
creased the F (Fig. 10), whereas high metabolic and secre-
tory intrinsic clearances within the segments as high
reduced F (Fig. 11). These findings mirrored those found for the TM
and SFM [137].
 19

CONCLUDING REMARKS
Model development of drug metabolism and transport by the intes-
tine is at the infancy stages. The efflux/absorptive transporters operate
in opposite directions at the apical membrane, with intestinal motil-
ity removing the drug in lumen to out of the body, thereby preventing
reabsorption and metabolism. The peculiarity in intestinal blood flow
to the active metabolic and absorptive further brings about the unique
aspect of route-dependent intestinal metabolism/excretion [139]. The
overall estimate of bioavailability is therefore, the result of membrane
permeation by different arrays of transporters operating in the same or
opposite directions, and preferential flow to cellular regions that con-
tain the enzymatic activities. Consequently, good correlation between
in vitro and in vivo data for intestinal drug metabolism/removal would
not be easy.
The present modeling approach had omitted the consideration of drug
dissolution kinetics. It is envisaged that modeling will be more complete
and improved upon coupling of the drug-release phase of the ACAT
model [132]. The intermittent release of drugs in various aggregated
and de-aggregated forms from the stomach, gastric emptying, bile salt
effects, and the presence of mucus may need to be considered. Proof of
20
21
22

the model relies not only on drug but also metabolite disposition during
both oral and systemic dosing. Needless to say, the liver should be
properly considered for first-pass removal and systemic bioavailability. It
is expected that the consolidation of physiologically-based intestinal and
liver models will greatly improve our predictiveness on drug absorption,
bioavailability and intestinal metabolism. The challenge remains in the
scale-up of the conceptual frameworks developed for the TM, SFM, SFM
and SSFM. The physiological parameters for the flow rate and volume,
as well as more appropriate intestinal transit times need to be properly
addressed for modeling of human absorption.

REFERENCES
1. W.I. Higuchi. Diffusional models useful in biopharmaceutics. Drug release rate
processes. J. Pharm. Sci. 56:315–324 (1967).
2. M.N. Martinez and G.L. Amidon. A mechanistic approach to understanding the
factors affecting drug absorption: a review of fundamentals. J. Clin. Pharmacol.
42:620–643 (2002).
3. M. Gibaldi, R.N. Boyes and S. Feldman. The influence of first pass effect on
availability of drugs. J. Pharm. Sci. 60:1338–1340 (1971).
4. M. Rowland. The influence of route of administration on drug availability. J.
Pharm. Sci. 101:70–74 (1972).
5. X. Xu, H. Hirayama and K.S. Pang. First pass metabolism of salicylamide.
Studies in the once through vascularly perfused rat intestine-liver preparation
Drug Metab. Dispos. 17:556–563 (1989).
6. H. Hirayama and K.S. Pang. First-pass metabolism of gentisamide: Influence of
intestinal metabolism on hepatic formation of conjugates. Studies in the once-
through vascularly perfused rat intestine-liver preparation. Drug Metab. Dispos.
18:580–578 (1990).
7. J. Chen and K.S. Pang. Effect of flow on first-pass metabolism of drugs: single
pass studies on 4-methylumbelliferone (4MU) conjugation in the serially per-
fused rat intestine and liver preparations. J. Pharmacol. Exp. Ther. 280:24–31
(1997).
8. R. Gugler, P. Lain and D.L. Azarnoff. Effect of portacaval shunt on the dis-
position of drugs with and without first-pass effect. J. Pharmacol. Exp. Ther.
195:416–423 (1975).
9. H. Hirayama, J. Morgado, I. Gasinska and K.S. Pang. Estimations of intestinal
and liver extraction in the in vivo rat: studies on gentisamide conjugation. Drug
Metab. Dispos. 18:580–587 (1990).
10. D.F. Magee and A.F. Dalley. II. In, Digestion and The Structure and Function
of The Gut. Karger Basel (1986).
11. L.S. Schanker, P. A. Shore, B.B. Brodie and C.A.M. Hogben. Absorption of drugs
from the stomach. I. The rat. J. Pharmacol. Exp. Ther. 120:528–539 (1957).
 23

12. L.S. Schanker, D.J. Tocco, B.B. Brodie, C.A.M. Hogben. Absorption of drugs
from the rat small intestine. J. Pharmacol. Exp. Ther. 121:81–88 (1958).
13. C.A.M. Hogben, D.J. Tocco, B.B. Brodie and L.S. Schanker. Absorption of drugs
from the stomach. II. The human. J. Pharmacol. Exp. Ther. 120:540–545 (1957).
14. C.A.M. Hogben, D.J. Tocco, B.B. Brodie and L.S. Schanker. On the mechanism
of intestinal absorption of drugs. J. Pharmacol. Exp. Ther. 125:275–282 (1959).
15. D. Winne. Shift of pH-absorptin curves. J. Pharmacokinet. Biopharm. 5:53–94
(1977).
16. A. Suzuki, W.I. Higuchi and N.F.H. Ho. Theoretical model studies of drug ab-
sorption and transport in the gastrointestinal tract. I. J. Pharm. Sci. 59:644–651
(1970).
17. A. Suzuki, W.I. Higuchi and N.F.H. Ho. Theoretical model studies of drug ab-
sorption and transport in the gastrointestinal tract. II. J. Pharm. Sci. 59:651–
659 (1970).
18. J.B. Dressman, G.L. Amidon and D. Fleisher. Absorption potential estimating
the fraction absorbed for orally administered compounds. J. Pharm. Sci. 74:588–
589 (1985).
19. P. Macheras M.Y. Symillides. Towards a quantitative approach for the predic-
tion of the fraction of dose absorbed using the absorption potential concept.
Biopharm. Drug Dispos. 10:43–53 (1989).
20. L.X. Yu, F. Lipka, J.R. Crison and G.L. Amidon. Transport approaches to the
biopharmaceutical design of oral drug delivery systems: prediction of intestinal
absorption. Adv. Drug Del. Rev. 19:359–376 (1996).
21. C.A. Lipinski, F. Lombardo, B.W. Dominy and P.J. Feeney. Experimental and
computational approaches to estimate solubility and permeability in drug dis-
covery and developmental settings. Adv. Drug Del. Rev. 23:3–25 (1997).
22. A.-L. Ungell, S. Nylander, S. Bergstrand, A. Sjoberg and H. Lennerns. Mem-
brane transport of drugs in different regions of the intestinal tract of the rat. J.
Pharm. Sci. 87:360–366 (1998).
23. C.W. Andrews, L. Bennet and L.X. Yu. Predicting human oral bioavailability
of a compound: development of a novel quantitative structural-bioavailabilty
relationship. Pharm. Res. 17:639–644 (2000).
24. U. Norinder, T. sterberg and P. Artursson. Theoretical calculation and predic-
tion of intestinal absorption of drugs in humans using MolSurf parametrization
and PLS statistics. Eur. J. Pharm. Sci. 8:49–56 (1999).
25. Y.H. Zhao, J. Le, M. Abraham, A. Hersey, P.J. Eddershaw, C.N. Luscombe, D.
Boutina, G. Beck, B. Sherborne, I. Cooper and J.A. Platts. Evaluation of human
intestinal absorption data and subsequent derivation of a quantitative structure-
activity relationship (QSAR) with the Abraham descriptors. J. Pharm. Sci.
90:749–784 (2001).
26. Y.H. Zhao, M.H. Abraham, J. Le, A. Hersey, C.N. Luscombe, G. Beck, B. Sher-
borne and I. Cooper. Rate-limited steps of human oral absorption and QSAR
studies. Pharm. Res. 19:1446–1457 (2002).
27. G. Klopman, L.R. Stefan and R.D. Saiakhov. ADME evaluation 2. A Computer
model for the prediction of intestinal absorption in humans. Eur. J. Pharm. Sci.
17:253–263 (2002).
24

28. Y.J. Fei, Y. Kanai, S. Nussberger, V. Ganapathy, F.H. Leibach, M.F. Romero,
S.K. Singh, W.F. Boron and M.A. Hedigerm. Expression cloning of a mammalian
proton-coupled oligopeptide transporter. Nature 368:563–566 (1994).
29. A. Tsuji and I. Tamai. Carrier-mediated intestinal transport of drugs. Pharm.
Res. 13:963–977 (1996).
30. W. Sadee, V, Drubbisch and G.L. Amidon. Biology of membrane transport
proteins. Pharm. Res. 12:1823–1837 (1995).
31. K. Ito, T. Iwatsubo, S. Kanamitsu, Y. Nakajima and Y. Sugiyama. Quantitative
prediction of in vivo drug clearance and drug interactions from in vitro data
on metabolism, together with binding and transport. Annu. Rev. Pharmacol.
Toxicol. 38:461–499 (1998).
32. L. Zhang, C.M. Brett and K.M. Giacomini. Role of organic cation transporters
in drug absorption and elimination. Annu. Rev. Pharmacol. Toxicol. 38:431–460
(1998).
33. H. Koepsell. Organic cation transporters in intestine, kidney, liver, and brain.
Annu. Rev. Physiol. 60:243–266 (1998).
34. K. Arimori and M. Nakano. Drug exsorption from blood into the gastrointestinal
tract. Pharm. Res. 15:371–376 (1998).
35. A.L. Craddock, M.W. Loe, R.W. Daniel, L.C. Kirby, H.C. Walters, M.H. Wong
and P.A. Dawson. Expression and transport properties of the human ileal and
renal sodium-dependent bile acid transporter. Am. J. Physiol. 274:G157–G169
(1998).
36. J.H. Lin, M. Chiba and T.A. Baillie. Is the role of the small intestine in first-pass
metabolism overemphasized? Pharmacol. Rev. 51:135–158 (1999).
37. H. Suzuki and Y. Sugiyama. Role of metabolic enzymes and efflux transporters
in the absorption of drugs from the small intestine. Eur. J. Pharm. Sci. 12:3–12
(2000).
38. V.J. Wacher, L. Salphati and L.Z. Benet. Active secretion and enterocytic drug
metabolism barriers to drug absorption. Adv. Drug Deliv. Rev. 46:89–102 (2001).
39. F. Thiebault, T. Tsuruo, H. Hamada, M.M. Gottesman, I. Pastan and M.C.
Willingham. Cellular localization of the multidrug-resistance gene product P-
glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. (USA) 84:7735–
7738 (1987).
40. S. Hsing, Z. Gatmaitan and I.M. Arias. The function of Gp170, the multidrug-
resistance gene product, in the brush border of rat intestinal mucosa. Gastroen-
terology 102:879–885 (1992).
41. J.W. Smit, A.H. Schinkel, M. Mller, B. Weert and D.K.F. Meijer. Contribution
of the murine mdr1a P-glycoprotein to hepatobiliary and intestinal elimination
of cationic drugs as measured in mice with an mdr1a gene disruption. Hepatology
27:1056–1063 (1998).
42. J.W. Smit, B. Weert, A.H. Schinkel and D.K.J. Meijer, D.K.J. Heterologous
expression of various P-glycoproteins in polarized epithelial cells induces direc-
tional transport of small (Type 1) and bulk (Type 2) cationic drugs. J. Phar-
macol. Exp. Ther. 286:321–327 (1998).
43. C.C. Paulusma, P.J. Bosma, G.J. Zaman, C.T. Bakker, M. Otter, G.L. Scheffer,
R.J. Scheper, P. Borst and R.P. Oude Elferink. Congenital jaundice in rats with
 25

a mutation in a multidrug resistance-associated protein gene. Science 271:1126–

1128 (1996).
44. Y. Gotoh, H. Suzuki, S. Kinoshita, T. Hirohashi, Y. Kato and Y. Sugiyama.
Involvement of an organic anion transporter (canalicular multispecific organic
an ion transporter/ multidrug resistance-associated protein 2) in gastrointestinal
secretion of glutathione conjugates in rats. J. Pharmacol. Exp. Ther. 292: 433–
439 (2000).
45. A.D. Mottino, T. Hoffman, L. Jennes and M. Vore. Expression and localization
of multidrug resistant protein MRP2 in rat small intestine. J. Pharmacol. Exp.
Ther. 293:717–723 (2000).
46. L.A. Doyle, W. Yang, L.V. Zbruzzo, T. Krogmann, Y. Gao, A.K. Rishi and D.D.
Ross. A multidrug resistance transporter from human MCF-7 breast cancer cells.
Proc. Natl. Acad. Sci. (USA) 95:15665–15670 (1998).
47. K. Miyake, L. Mickley, T. Litman, Z. Zhan, R. Robey, B. Cristensen, M. Brangi,
L. Greenberger, M. Dean, T. Fojo and S.E. Bastes, S.E. Molecular cloning of
cDNAs which are highly overexpressed in mitoxanthrone-resistant cells: Demon-
stration of homology to ABC transport genes. Cancer Res. 59:8–13 (1999).
48. J.W. Jonker, J.W. Smit, F. Brinkhuis, M. Maliepaard, J.H. Beijnen, J.H.M.
Schellens and A.H. Schinkel. Role of breast cancer resistance protein in the
bioavailability and fetal penetration of topotecan. J. Natl. Canc. Inst. 92:1651–
1656 (2000).
49. J.D. Allen, R.F. Brinkhuis, J. Wijnholds and A.F. Schinkel. The mouse
Bcrp1/Mxr/Abcp gene: Amplication and overexpression in cell lines selected for
resistance to topotecan, mitoxantrone, or doxorubicin. Cancer Res. 59:4237–
4241 (1999).
50. J.D. Allen, A. van Loevezijn, J.M. Lakhai, N. van der Valk, O. van Tellingen,
G. Reid, J.H.M. Schellens, F.-J. Koomen and A.F. Schinkel. Potent and specific
inhibition of the breast cancer resistance protein multidrug transporter in vitro
and in mouse intestine by a novel analogue of fumitremorgin C. Molec. Canc.
Ther. 1:417–425 (2002).
51. C.P. Zamber, J.K. Lamba, K. Yasuda, J. Farnum, K. Thummel, J.D. Scheutz and
E.G. Schuetz. Natural allelic variants of breast cancer resistance protein (BCRP)
and their relationship to BCRP expression in human intestine. Pharmacogenetics
13:19–28 (2003).
52. H. Saitoh, C. Gerard and B.J. Aungst. The secretory intestinal transport of some
beta-lactam antibiotics and anionic compounds: A mechanism contributing to
poor oral absorption. J. Pharmacol. Exp. Ther. 278:205–211 (1996).
53. K.S. Lown, R.R. Mayo, A.B. Leichtman, H.-L. Hsiao, K. Turgeon, P. Schmiedin-
Ren, M.B. Brown, W. Guo, S.J. Rossi, L.Z. Benet and P.B. Watkins. Role of
intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavail-
ability of cyclosporine. Clin. Pharmacol. Ther. 62:48–60 (1997).
54. R.B. Kim, M.F. Fromm, C. Wandel, B. Leake, A.J.J. Wood, D.M. Roden and
G.R. Wilkinson. The drug transporter P-glycoprotein limits oral absorption and
brain entry of HIV-1 protease inhibitors. J. Clin. Invest. 101:289–294 (1998).
55. H.C. Walters, A.L. Craddock, H. Fusegawa, M.C. Willingham and P.A. Dawson.
Expression, transport properties, and chromosomal location of organic anion
transporter subtype 3. Am. J. Physiol. 279:G1188–G1200 (2000).
26
56. M.N. Orsengio, M. Tosco, C. Bazzini, U. Laforenza and A. Faelli. A monocarbo-
cylate transporter MCT1 is located at the basolateral pole of rat jejunum. Exp.
Physiol. 84:1033–1042 (1999).
57. I. Tamai, Y. Sai, A. Ono, Y. Kido, H. Yabuuchi, H. Takanaga, E. Satoh, T.
Ogihara, O. Amano, S. Izeki and A. Tsuji. Immunohistochemical and functional
characterization of pH-dependent intestinal absorption of weak organic acids by
the monocarboxylic acid transporter MCT1. J. Pharm. Pharmacol. 51:1113–
1121 (1999).
58. H. Hoensch, C.H. Woo and R. Schmid. Cytochrome P450 and drug metabolism
in intestinal villous and crypt cells of rats. Effects of dietary iron. Biochem.
Biophys. Res. Commun. 65:399–406 (1975).
59. R.K. Dubey and J. Singh. Localization and characterization of drug-
metabolizing enzymes along the villus-crypt surface of the rat small intestine
I. Monooxyenases Biochem. Pharmacol. 37:169–176 (1988).
60. P.B. Watkins, S.A. Wrighton, E.G. Schuetz, D.T. Molowa and P.S. Guzelian.
Identification of glucocorticoid-inducible cytochrome P-450 in the intestinal mu-
cosa of rats and man. J. Clin. Invest. 80:1029–1036 (1987).
61. J.C. Kolars, P. Schmiedin-Ren, J.D. Schuetz, C. Fang and P.B. Watkins. Iden-
tification of rifampin-inducible P450IIIA4 (CY3A4) in human small bowel en-
terocytes. J. Clin. Invest. 90:1871–1878 (1992).
62. M.F. Paine, D.D. Shen, K.L. Kunze, J.D. Perkins, C.L. Marsh, J.P. McVicar,
D.M. Barr, B.S. Gilles and K.E. Thummel. First-pass metabolism of midazolam
by the human intestine. Clin. Pharmacol. Ther. 60:14–24 (1996).
63. M.F. Paine, M. Khalighi, J.M. Fisher, D.D. Shen, K.L. Kunze, C.L. Marsh, J.D.
Perkins and K.E. Thummel. Characterization of interintestinal and intraintesti-
nal variations in human CYP3A-dependent metabolism. J. Pharmacol. Exp.
Ther. 283:1552–1562 (1997).
64. K.W. Thummel, D. O’Shae, M.F. Paine, D.D. Shen, K.L. Kunze, J.D. Perkins
and G.R. Wilkinson. Oral first pass elimination of midazolam involves both
gastrointestinal and hepatic CYP3A-mediated metabolism. Clin. Pharmacol.
Ther. 59:491–502 (1996).
65. K.F. Ilett, L.B. Tee, P.T. Reeves and R.F. Minchin. Metabolism of drugs and
other xenobiotics in the gut lumen and wall. Pharmac. Ther. 46:67–93 (1990).
66. R.K. Dubey and J. Singh. Localization and characterization of drug-
metabolizing enzymes along the villus-crypt surface of the rat small intestine
II. Conjugases Biochem. Pharmacol. 37:177–184 (1988).
67. T. Terao, E. Hisanaga, Y. Sai, I. Tamai and A. Tsuji. Active secretion of drugs
from the small intestine epithelium in rats by P-glycoprotein functioning as an
absorption barrier. J. Pharm. Pharmacol. 48:1083–1089 (1996).
68. V.J. Wacher, J.A. Silverman, Y. Zhang and L.Z. Benet. Role of P-glycoprotein
and cytochrome P450 3A in limiting oral absorption of peptides and pep-
tidomimetics. J. Pharm. Sci. 87:1322–1330 (1998).
69. L.Z. Benet and C.L. Cummins. The drug efflux-metabolism alliance: biochemical
aspects. Adv. Drug Del. Rev. 50:S3-S11 (2001).
70. H. Saitoh and B.J. Aungst. Possible involvement of multiple P-glycoprotein
mediated efflux systems in the transport of verapamil and other organic cations
across rat intestine. Pharm. Res. 12:1304–1310 (1995).
 27

71. R. Sandström, A. Karlsson and H. Lennernäs. The absence of stereoselective

P-glycoprotein-mediated transport of R/S-verapamil across the rat jejunum. J.
Pharm. Pharmacol. 50:729–735 (1998).
72. B.-L. Leu and J.-D. Huang. Inhibition of intestinal P-glycoprotein and effects
on etoposide absorption. Cancer Chemother. Pharmacol. 35:432–436 (1995).
73. D.S. Sonnichsen, Q. Liu, E.G. Schuetz, J.D. Schuetz, A. Pappo and M.V. Relling.
Variability in human cytochrome P450 paclitaxel metabolism. J. Pharmacol.
Exp. Ther. 275:566–575 (1995).
74. A. Nakayama, H. Saitoh, M. Oda, M. Takada and B.J. Aungst. Region-
dependent disappearance of vinblastine in the rat small intestine and charac-
terization of its P-glycoprotein-mediated efflux system. Eur. J. Pharm. Sci.
11:317–324 (2000).
75. I. Chico, M.H. Kang, R. Bergan, J. Abraham, S. Bakke, B. Meadows, A. Rutt,
R. Robey, P. Choyke, M. Merino, B. Goldspiel, T. Smith, S. Steinberg, W.D.
Figg, T. Fojo and S. Bates. Phase I study of infusional paclitaxel in combination
with the P-glycoprotein antagonist PSC 833. J. Clin. Oncol. 19:832–842 (2001).
76. J. Abraham, S. Bakke, A. Rutt, B. Meadows, M. Merino, R. Alexander, D.
Schrump, D. Bartlett, P. Choyke, R. Robey, E. Hung, S.M. Steinberg, S. Bates
and T. Fojo. A phase II trial of combination chemotherapy and surgical resection
for the treatment of metastatic adrenocortical carcinoma: continuous infusion
doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein
antagonist. Cancer 94:2333–2343 (2002).
77. M.E. Cavet, M. West and N.L. Simmons. Transport and epithelial secretion of
the cardiac glycoside, digoxin, by human intestinal epithelial (Caco-2) cells. Br.
J. Pharmacol. 118:1389–1396 (1996).
78. B. Greiner, M. Eichelbaum, P. Fritz, H.P. Kreichgauer, O. von Richter, J.
Zundler and H.K. Kroemer. The role of intestinal P-glycoprotein in the interac-
tion of digoxin and rifampin. J. Clin. Invest. 104:147–153 (1999).
79. J.H. Hochman, M. Chiba, J. Nishime, M. Yamazaki and J.H. Lin. Influence of
P-glycoprotein on the transport and metabolism of indinavir in Caco-2 cells ex-
pressing cytochrome P-450 3A4. J. Pharmacol. Exp. Ther. 292:310–318 (2000).
80. J.H. Hochman, M. Chiba, M. Yamazaki, C. Tang and J.H. Lin. P-glycoprotein
mediated efflux of indinavir metabolites in Caco-2 cells expressing cytochrome
P-450 3A4. J. Pharmacol. Exp. Ther. 298:323–330 (2001).
81. L.Y. Li, G.L. Amidon, J.S. Kim, T. Heimbach, F. Kesisoglou, J.T. Topliss and D.
Fleisher. Intestinal metabolism promotes regional differences in apical uptake of
indinavir: coupled effect of P-glycoprotein and cytochrome P450 3A on indinavir
membrane permeability. J. Pharmacol. Exp. Ther. 301:586–593 (2002).
82. L.-S. Gan, M.A. Moseley, B. Khoosla, P.P.F. Augustijns, T.P. Bradshow,
R.W. Hendren and D.R. Thakker. CYP3A-like cytochrome P-450 mediated
metabolism and polarized efflux of cyclosporin A in Caco-2 cells interaction
between the biochemical barriers to intestinal transport. Drug Metab. Dispos.
24:344–349 (1996).
83. A. Lampen, W. Christians, P.F. Guengerich, P.B. Watkins, J. Kolars, A. Bader,
A.-K. Gonschior, H. Dralle, I. Hackbarth and K.-F. Sewing. Metabolism of the
immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug
28

interactions and interindividual variability. Drug Metab. Dispos. 23:1315–1324

(1995).
84. Y. Hashimoto, H. Sasa, M. Shimomura and K.-I. Inui. Effects of intestinal and
hepatic metabolism on the bioavailability of tacrolimus in rats. Pharm. Res.
15:1609–1613 (1998).
85. T. Hashida, S. Masuda, S. Uemoto, H. Saito, K. Tanaka and K. Inui. Pharma-
cokinetic and prognostic significance of intestinal MDR1 expression in recipients
of living-donor liver transplantation. Clin. Pharmacol. Ther. 69:308–316 (2001).
86. A. Lampen, Y. Zhang, I. Hackbarth, L.Z. Benet K.-Fr. Sewing and U. Christians.
Metabolism and transport of the macrolide sirolimus in the small intestine. J.
Pharmacol. Exp. Ther. 285:1104–1112 (1998).
87. M.F. Paine, L.Y. Leung, H.K. Lim, K. Liao, A. Oganesian, M.Y. Zhang, K.E.
Thummel and P.B. Watkins. Identification of a novel route of extraction of
sirolimus in human small intestine: roles of metabolism and secretion. J. Phar-
macol. Exp. Ther. 301:174–186 (2002).
88. S.A. Kliewer, J.T. Moore, L. Wade, J.L. Staudinger, M.A. Watson, S.A. Jones,
D.D. McKee, B.B. Oliver, T.M. Willson, R.H. Zetterstrom, T. Perlmann and J.
Lehmann. An orphan nuclear receptor activated by pregnanes defines a novel
steroid signalling pathway. Cell 92:73–82 (1998).
89. H. Zhang, E. LeCulyse, L. Liu, M. Hu, L. Matoney, W. Zhu and B. Yan. Rat
pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic reg-
ulation. Arch. Biochem. Biophys. 368:14–22 (1999).
90. K.S. Pang and M. Chiba. Metabolism: Scaling up from in vitro to organ and
whole body. In: Welling, P.G. and Balant, L.P. (eds.), Handbook of Experimental
Pharmacology, Springer-Verlag, Stuttgart, 1994, pp. 101–187.
91. T.N. Abu-Zahra and K.S. Pang. Effect of zonal transport and metabolism on
hepatic removal: enalapril hydrolysis in zonal, isolated rat hepatocytes in vitro
and correlation with perfusion data. Drug Metab. Dispos. 28:807–813 (2000).
92. A.A. Raoof, J. Butler and J.G. Devane. Assessment of regional differences in
intestinal fluid movement in the rat using modified in situ single pass perfusion
model. Pharm. Res. 15:1314–1316 (1998).
93. T. Gramatté and K. Richter. Paracetamol absorption from different sites in the
human small intestine. Br. J. Clin. Pharmacol. 37:608–611 (1994).
94. T. Gramatté. Griseofulvin absorption from different sites in the human small
intestine. Biopharm. Drug Dispos. 15:747–759 (1996).
95. T. Gramatté, E. El Desoky and U. Klotz. Site-dependent small intestinal ab-
sorption of ranitidine. Eur. J. Clin. Pharmacol. 46:253–259 (1994).
96. T. Gramatté, R. Oertel, B. Terhaag and W. Kirch. Direct demonstration of small
intestinal secretion and site-dependent absorption of the beta-blocker talinolol
in humans. Clin. Pharmacol. Ther. 59:541–549 (1996).
97. W. Homsy, G. Caille, P. du Souich. The site of absorption in small intestine
determines diltiazem bioavailability in rabbit. Pharm. Res. 12:1722–1726 (1995).
98. H. Lennarnäs. Human intestinal permeability. J. Pharm. Sci. 87:403–410 (1998).
99. J. Hunter, M.A. Jepson, T. Tsuruo, N.L. Simmons and B.H. Hirst. Functional
expression of P-glycoprotein in apical membranes of human intestinal Caco-2
Cells. J. Biol. Chem. 268:14991–14997 (1990).
 29

100. V.D. Makhey, A. Guo, D.A. Norris, P. Hu, J. Van and P.J. Sinko. Characteri-
zation of the regional intestinal characteristics and in Caco-2 cells. Pharm. Res.
15:1160–1167 (1998).
101. B.L. Schneider, P.A. Dawson, D.M. Christie, W. Hardikar, M.H. Wong and F.J.
Suchy. Cloning and molecular characterization of the ontogeny of a rat ileal
sodium-dependent bile acid transporter. J. Clin. Invest. 95:745–754 (1995).
102. L.Y. Ngo, S.D. Patil and J.D. Unadkat. Ontogenic and longitudinal activity of
Na+-nucleoside transporters in the human intestine. Am. J. Physiol. 280:G475-
G481 (2001).
103. D. Cong, A.K.Y. Fong, R. Lee and K.S. Pang. Absorption of benzoic acid (BA)
by segmental regions of the in situ perfused rat small intestine. Drug Metab.
Dispos. 29:1539–1547 (2001).
104. M.H. Wong, P. Oelkers, A.L. Craddock and P.A. Dawson. Expression cloning
and characterization of the hamster ileal sodium-dependent bile acid transporter.
J. Biol. Chem. 269:1340–1347 (1994).
105. J. Chianale, V. Vollrath, A.M. Widlandt, S. Miranda, R. Gonzalez, A.M. Fresno,
C. Quintana, S. Gonzalez, L. Andrade and S. Guzman. Differences between
nuclear run-off and mRNA levels for multidrug resistance gene expression in the
cephalocaudal axis of the mouse intestine. Biochim. Biophys. Acta 1264:369–376
(1995).
106. A. Collett, N.B. Higgs, E. Sims, M. Rowland and G. Warhurst, G. Modula-
tion of the permeability of H2 receptor antagonists cimetidine and ranitidine
by P-glycoprotein in rat intestine and the human colonic cell line Caco-2. J.
Pharmacol. Exp. Ther. 288:171–178 (1999).
107. R.H. Stephens, C.A. O’Neill, A. Warhurst, G.L. Carlson, M. Rowland and G.
Warhurst. Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and
human intestinal epithelia. J. Pharmacol. Exp. Ther. 296:584–591 (2001).
108. D. Rost, S. Mahner, Y. Sugiyama and Y. Stremmel. Expression and localization
of the multidrug resistance-associated protein 3 in rat small and large intestine.
Am. J. Physiol. 282:G720-G726 (2002).
109. L.R. Schwarz and M. Schwenk. Sulfation in isolated enterocytes of guinea pig:
dependence of inorganic sulfate. Biochem. Pharmacol. 33:3353–3356 (1984).
110. G. Clifton and N. Kaplowitz. The glutathione S-transferases of the small intes-
tine in the rat. Cancer Res. 37:788–791 (1977).
111. L.M. Pinkus, J.N. Ketley and W.B. Jakoby. The glutathione S-transferases as a
possible detoxification system of rat intestinal epithelium. Biochem. Pharmacol.
26:2359–2363 (1977).
112. M. Doherty and K.S. Pang. Route-dependent metabolism of morphine in the
vascularly perfused rat small intestine preparation. Pharm. Res. 17:290–297
(2000).
113. Y. Wen, R.P. Remmel and C.L. Zimmerman. First-pass disposition of (-)-6-
aminocarbovir in rats. I. Prodrug activation may be limited by access to enzyme.
Drug Metab. Dispos. 7:113–121 (1999).
114. P.B. Watkins, S.A. Murray, L.G. Winkelman, D.M. Heuman, S.A. Wrighton and
P.S. Guzelian. Erythromycin breath test as an assay of glucuocorticoid-inducible
liver cytochrome P-450. J. Clin. Invest. 83:688–697 (1989).
30
115. K.S. Lown, J.C. Kolars, K.E. Thummel, J.L. Barnett, K.L. Kune, S.A. Wrighton
and P.B. Watkins. Interpatient heterogeneity in expression of CYP3A4 and
CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test.
Drug Metab. Dispos. 22:947–955 (1994).
116. M. Doherty and K.S. Pang. The role of the intestine in the absorption and
metabolism of drugs. Drug Chem. Toxicol. 20:329–344 (1997).
117. P.G. Welling. Effects of gastrointestinal disease on drug absorption. In: L.Z.
Benet, N. Massoud, and J.G. Gambertoglio. (eds.), Pharmadynamic Basis for
Drug Treatment. Raven Press, New York, 1984, pp. 29–47.
118. T. Kimura and K. Higaki. Gastrointestinal transit and drug absorption. Biol.
Pharm. Bull. 25:149–164 (2002).
119. S.I. Terry, J.C. Gould, J.P. McManus and L.F. Prescott. Absorption of penicillin
and paracetamol after small intestinal bypass surgery. Eur. J. Clin. Pharmacol.
23:245–248 (1982).
120. H.M. Ali. Reduced ampicillin bioavailability following oral coadministration with
chloroquine. J. Antimicrob. Chemother. 15:781–784 (1985).
121. N. Aoyagi, H. Ogaa, N. Kaniwa and A. Ejima. Bioavailability of griseofulvin
plain tablets in stomach-emptying controlled rabbits and the correlation with
bioavailability in humans. J. Pharmacbiodyn. 7:630–640 (1984).
122. T. Hamaguchi, D. Shinkuma, T. Irie, Y. Yamanaka, Y. Morita, B. Iwamoto,
K. Miyoshi, K. and N. Mizuno. Effect of a high-fat meal on the bioavailability
of phenytoin in a commercial powder with a large particle size. Int. J. Clin.
Pharmacol. Ther. 31:326–330 (1993).
123. R.L. Choi, J.X. Sun and G.M. Kochak, G.M. The effect of food on the relative
bioavailability of fadrozole hydrochloride. Biopharm. Drug Dispos. 14:779–784
(1993).
124. K.S. Pang. Modeling of intestinal drug absorption: Roles of transporters and
metabolic enzymes. A review. Drug Metab. Dispos. (in press).
125. C.L. Cummins, L.M. Mangravite and L.Z. Benet. Characterizing the expres-
sion of CYP3A4 and efflux transporters (P-gp, MRP1, MRP2) in CYP3A4-
transfected Caco-2 cells after induction with sodium butyrate and the phorbol
ester 12-O-tetradecanoylphorbol-13-acetate. Pharm. Res. 18:1102–1109 (2001).
126. B.M. Johnson, W.N. Charman and C.J.H. Porter. The impact of P-glycoprotein
efflux on enterocyte residence time and enterocyte-based metabolism of vera-
pamil. J. Pharm. Pharmacol. 53:1611–1619 (2001).
127. D. Tam, H. Sun and K.S. Pang. Influence of P-glycoprotein, transfer clearances,
and drug binding on intestinal metabolism in Caco-2 monolayers or membrane
preparations. A theoretical analysis. Drug Metab. Dispos. 31:1214–1226 (2003).
128. M. Gibaldi and D. Perrier. Pharmacokinetics, Second Edition, Marcel Dekker,
New York, 1982.
129. K.K. Chan and M. Gibaldi. Assessment of drug absorption after oral adminis-
tration. J. Pharm. Sci. 74:388–393 (1985).
130. L.X. Yu and G.L. Amidon. Saturable small intestinal drug absorption in humans:
modeling and intrepretation of ceftrizine data. Eur. J. Pharmaceut. Biopharm.
45:199–203 (1998).
 31
131. L.X. Yu and G.L. Amidon. A compartmental absorption and transit time model
for estimating oral drug absorption. Int. J. Pharmaceut. 186:119–125 (1999).
132. A. Agoram, W.S. Woltosz and M.B. Bolger. Predicting the impact of physio-
logical and biochemical processes on oral drug absorption. Adv. Drug Del. Rev.
50:S41–S67 (2001).
133. K. Ito, H. Kusuhara and Y. Sugiyama. Effects of intestinal CYP3A4 and
P-glycoprotein on oral drug absorption - Theoretical approach. Pharm. Res.
16:225–231 (1999).
134. K.S. Lown, D.G. Bailey R.J. Fontana, S.K. Janardan, C.H. Adair, L.A. Fortlage,
M.B. Brown, W. Guo and P.B. Watkins. Grapefruit juice increases felodipine
oral availability in humans by decreasing intestinal protein expression. J. Clin.
Invest. 99:2545–2553 (1997).
135. D.G. Bailey, J.M. Arnold, H.A. Strong, C. Munoz and J.D. Spence. Effect of
grapefruit juice and naringin on nisoldipine pharmacokinetics. Clin. Pharmacol.
Ther. 54:589–594 (1993).
136. G.K. Dresser, D.G. Bailey, B.F. Leake, U.I. Schwarz, P.A. Dawson, D.J. Free-
man and R.B. Kim. Fruit juices inhibit organic anion transporting polypeptide-
mediated drug uptake to decrease the oral availability of fexofenadine. Clin.
Pharmacol. Ther. 71:11–20 (2002).
137. K.S. Pang, E. Tseng and D. Tam. Differences between the traditional physio-
logical model (TM) and the segregated flow model (SFM) on the area under the
curves, mean residence time, intestinal metabolism and bioavailability, (submit-
ted).
138. P.J. Klippert and J. Noordhoek. The area under the curve of metabolites for
drugs and metabolites cleared by the liver and extrahepatic organs. Its depen-
dence on the administration route of precursor drug. Drug Metab. Dispos. 13:97–
101 (1985).
139. D. Cong, M. Doherty and K.S. Pang. A new physiologically-based segregated
flow model to explain route-dependent intestinal metabolism. Drug Metab. Dis-
pos. 28:224–235 (2000).
140. J. Svanvik. Mucosal blood circulation and its influence on passive absorption of
the small intestine. Acta Physiol. Scand. Suppl. 385:1–44 (1973).
141. D.N. Granger, D.I. Richardson, P.R. Kvietys and N.A. Mortillard. Intestinal
blood flow. Gastroenterology 78:837–863 (1980).
142. S. MacFerran and D. Mailman. Effects of glucagon on canine intestinal sodium
and water fluxes and regional blood flow. J. Physiol. 266:1–12 (1977).
143. D. Mailman Effects of vasoactive intestinal polypeptide on intestinal absorption
and blood flow. J. Physiol. 279:121–132 (1978).
144. G.L. Sirianni and K.S. Pang. Organ clearance concepts: New perspectives on
old principles. J. Pharmacokinet. Biopharm. 25:457–478 (1997).
145. E.G. Schuetz and A.H. Schinkel. Drug disposition as determined by the interplay
between drug-transporting and drug-metabolizing systems. J. Biochem. Mol.
Toxicol. 13:219–222 (1999).
146. D. Tam, R.G. Tirona and K.S. Pang. Segmental intestinal transporters and
metabolic enzymes on intestinal drug absorption. Drug Metab. 31:373–383
(2003).
32

147. P.G. Traber, D.L. Gumucio and W. Wang. Isolation of intestinal epithelial cells
for the study of differential gene expression along the crypt-villus axis. Am. J.
Physiol. 260:G895–G903 (1991).
148. D. Tam, H. Sun and K.S. Pang. Influence of P-glycoprotein, transfer clearances,
and drug binding on intestinal metabolism in Caco-2 monolayers or membrane
preparations. A theoretical analysis. Drug Metab. Dispos. 31:1214–1226 (2003)
149. A. Tsuji and I. Tamai. Na+ and pH dependent transport of foscarnet via the
phosphate carrier system across intestinal brush border vesicles. Biochem. Phar-
macol. 38:1019–1022 (1989)
150. R. Aldini, M. Montagnani, A. Roda, S. Hrelia, P.L. Biagi and E. Roda. Intestinal
absorption of bile acids in the rabbit. Different transport rates in jejunum and
ileum. Gastroenterology 110:459–468 (1996)
151. S.M. Huijghebaer, S.M. Sim D.J. Back and H.J. Eyssen. Distribution of estrone
sulfatase activity in the intestine of germfree and conventional rats. J. Steroid
Biochem. 20:1175–1179 (1984)
152. A.S. Koster, A.C. Frankhuijzen-Sierevogel and J. Noordhoek. Glucuronidation
of morphine and six in isolated rat intestinal epithelial
cells. Drug Metab. Dispos. 13:232–237 (1985)
153. M.P. Ducharme, L.H. Warbasse and D.J. Edwards. Disposition of intravenous
and oral cyclosporine after administration with grapefruit juice. Clin. Pharma-
col. Ther. 57:485–491 (1995)
154. I. Soria and C.L. Zimmerman. In vivo bioavailability predictions from perfused
intestine studies. Int. J. Clin. Pharmacol. Ther. 34:90–91 (1996).
155. N. Vidon, D. Evard, J. Godbillon, M. Rongier, M. Duval, J.P. Schoeller, J.J.
Bernier, and J. Hirtz. Investigation of drug absorption from the gastrointestinal
tract of man. II. Metoprolol in the jejunum and ileum. Br. J .Clin. Pharmacol.
19(S2):107S–112S (1996).
156. A.B. Suttle and K.L. Brouwer. Gastrointestinal transit and distribution of ran-
itidine in the rat. Pharm. Res. 12:1316–1322 (1995).
157. K.S. Pang, V. Yuen, S. Fayz, J.M. te Koppele, and G.J. Mulder, G.J. Absorption
and metabolism of acetaminophen by the in situ perfused rat small intestine
preparation. Drug Metab. Dispos. 14:102–111 (1986).
158. K.S. Pang, W.F. Cherry, and E.H. Ulm. Disposition of enalapril in the perfused
rat intestine-liver preparation: absorption, metabolism and first-pass effect. J.
Pharmacol. Exp .Ther. 233:788–795 (1985).