doi: 10.1111/j.1472-8206.2004.00291.

REVIEW Functional interaction of intestinal CYP3A4

ARTICLE
and P-glycoprotein
Kari T. Kivistöa*, Mikko Niemia, Martin F. Frommb
a
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
b
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Nuremberg,
Germany

Keywords
absorption,
bioavailability,
CYP3A4,
P-glycoprotein
Received 6 July 2004;
revised 1 August 2004;
accepted 6 September 2004
*Correspondence and reprints:
kari.kivisto@ikp-stuttgart.de
ABSTRACT
Intestinal CYP3A4-mediated biotransformation and active efflux of absorbed drug
by P-glycoprotein are major determinants of bioavailability of orally administered
drugs. The hypothesis that CYP3A4 and P-glycoprotein may act in concert to limit
oral drug bioavailability is attractive from a theoretical point of view. Evidence in
support of such an interplay between CYP3A4 and P-glycoprotein comes mainly
from a limited number of in vitro and animal studies. Obviously, it is a challeng-
ing task to demonstrate in vivo in humans that the function of CYP3A4 and
P-glycoprotein in enterocytes is complementary, and results to directly support this
concept remain elusive. However, CYP3A4 and P-glycoprotein are clearly an
integral part of an intestinal defence system to protect the body against harmful
xenobiotics, and drugs that are substrates of both proteins often have a low
bioavailability after oral administration. The functional interaction of intestinal
CYP3A4 and P-glycoprotein warrants additional study. Further understanding this
interplay would be potentially useful during drug development to solve bioavail-
ability problems of new drug entities.

extruded from inside the enterocytes into the intestinal

INTRODUCTION
Intestinal oxidative biotransformation and active efflux
of absorbed drug are now recognized as major determi-
nants of bioavailability of orally administered drugs.
CYP3A4 is localized in the human small intestine to the
columnar epithelial cells lining the intestinal lumen [1]
and P-glycoprotein is found on the apical surface (that is,
luminal entrance site) of these cells [2,3]. That CYP3A4
and P-glycoprotein may act synergistically in the small
intestine to limit oral drug bioavailability is suggested
not only by their joint presence at sites of drug
absorption (and elimination) but also by the extensive
overlap in their substrate specificities [4–7]. The function
of P-glycoprotein may allow CYP3A4 to have repeated
and prolonged access to its substrate molecules [7,8].
In other words, a portion of the xenobiotic molecules
lumen by the P-glycoprotein can be reabsorbed into the
enterocytes and is thus exposed again to CYP3A4.
Furthermore, P-glycoprotein might prevent further
interaction of CYP3A4-generated metabolites with the
enzyme (which might result in product inhibition) by
extruding them out of the enterocytes [9,10]. Some
examples of drugs that are substrates of both CYP3A4
and P-glycoprotein are given in Table I [11,12]. It is
noteworthy that drugs that are substrates of both
proteins often have a low oral bioavailability. Further
understanding the background of the interactive nature
of intestinal CYP3A4 and P-glycoprotein will therefore
be important also in controlling and improving oral
bioavailability of CYP3A4/P-glycoprotein substrates [8].
The purpose of this review is to briefly summarize the
current knowledge regarding the functional interaction

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622 K. T. Kivistö et al.

Table I Selected substrates of P-glycoprotein. of intestinal CYP3A4 and P-glycoprotein. As it is very

difficult to prove directly in humans that these proteins
P-glycoprotein substrate CYP3A4 substratea
have synergistic actions in limiting the bioavailability of
Anticancer agents orally administered drugs, most studies that have inves-
Docetaxel + tigated this hypothesis have relied on in vitro or animal
Etoposide +
experiments.
Imatinib +
Paclitaxel +
Teniposide +
INTESTINAL CYP3A4
Vinblastine +
Vincristine + CYP3A4, the major isoform of the CYP3A subfamily, is
Beta-blockers one of the most important drug-metabolizing enzymes
Bunitrolol )
in humans. CYP3A4 has a very broad substrate
Carvedilol +
Celiprolol )
specificity and is involved in the phase I metabolism
Talinolol ) of about 50% of currently used drugs. The primary site
Calcium-channel blockers of expression of CYP3A4 is the liver, but intestinal
Diltiazem + enterocytes also contain high amounts of CYP3A4
Mibefradil + [1,13,14]. CYP3A4-mediated biotransformation in the
Verapamil +
gut wall has been shown to substantially contribute to
Other cardiovascular drugs
Digitoxin )
the overall first-pass metabolism of a large number of
Digoxin ) therapeutic drugs [15–21]. For example, a pharmaco-
Quinidine + kinetic study in healthy volunteers showed that the
HIV protease inhibitors first-pass extraction ratios of oral midazolam for the
Amprenavir + gut and liver were comparable (43 and 44%, respect-
Indinavir +
ively, yielding an overall oral bioavailability of about
Nelfinavir +
Saquinavir +
30%) [20]. Similar results were later directly obtained
Ritonavir + for verapamil with a multilumen intestinal perfusion
Corticosteroids catheter in healthy subjects [21]. On the contrary, it
Dexamethasone + has been argued that the role of intestinal drug
Methylprednisolone + metabolism in the first-pass effect may have been
Immunosuppressants
overemphasized [22]. This view was based on problems
Cyclosporin +
Sirolimus +
inherent in the methodology available for determin-
Tacrolimus + ation of in vivo intestinal first-pass metabolism in
Antiemetic drugs humans and the fact that the total CYP3A4 content of
Ondansetron + the human small intestine is small compared with that
Antibiotics of the liver [13]. This apparent discrepancy may partly
Erythromycin +
lie in the anatomical localization of intestinal CYP3A4
Levofloxacin )
Statins
expression [14,22]. Duodenal and proximal jejunal
Atovastatin + mucosa, which are readily exposed to drug molecules
Lovastatin + dissolved in the gastric and intestinal contents, are rich
Antihistamines in villi, the tips of which are lined with mature
Fexofenadine ) CYP3A4-containing enterocytes [1]. This strategic
Terfenadine +
localization of CYP3A4 provides the first site for
Other drugs
metabolism of orally ingested drugs. We recently found
Amitriptyline +
Itraconazole + a much higher CYP3A4 protein content in enterocytes
Losartan ) isolated from human duodenal or jejunal mucosa
Morphine + compared with CYP3A4 content in liver samples
Phenytoin ) obtained from the same subjects [14]. This study thus
Rifampin +
lends further support to the view that metabolism in
a
Indicates whether P-glycoprotein substrates are (+) or are not ()) substrates the gut wall substantially contributes to the overall
of CYP3A4 ([11,12] and references therein). first-pass metabolism of many CYP3A4 substrates.

Ó 2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 621–626

CYP3A4 and P-glycoprotein
INTESTINAL P-GLYCOPROTEIN
P-glycoprotein is a plasma membrane-bound glyco-
protein that belongs to the superfamily of ATP-binding
cassette (ABC) transporters [23,24]. P-glycoprotein, the
encoded product of the ABCB1 (MDR1) gene, serves as
a drug efflux pump that decreases intracellular drug
concentrations. The significance of P-glycoprotein as
a xenobiotic efflux pump was first realized when it
was found that cancer cells expressing P-glycoprotein
are resistant to a large number of anticancer drugs
(multidrug resistance, MDR) as a result of active
extrusion of anticancer agents out of the tumour cells
[25]. P-glycoprotein is also widely expressed in healthy
tissues, limiting entry (absorption) of drugs and other
xenobiotics into the body and specific anatomical
compartments and facilitating their elimination. Drug
absorption was previously considered to be essentially a
passive process dependent mainly on the physicochem-
ical characteristics of the drug (e.g. lipophilicity).
However, it is now well established that efflux drug
transporters such as the P-glycoprotein may reduce
drug absorption [26,27]. P-glycoprotein, which is
localized to the apical membrane of the epithelial cells
lining the intestinal lumen [2,3], is recognized as a
major factor limiting drug bioavailability [27–32]. In
contrast to CYP3A4, the expression of P-glycoprotein
appears to increase progressively along the length of
intestine [22,33]. Like CYP3A4, P-glycoprotein exhibits
a very broad substrate specificity, consistent with a role
in transporting compounds absorbed into the entero-
cytes back into the intestinal lumen.
CO-REGULATION OF CYP3A4 AND
P-GLYCOPROTEIN
Several studies have shown that intestinal and hepatic
CYP3A4 enzymes are not co-ordinately regulated
[28,34]. This seems to be the case also with P-glyco-
protein [14]. As common regulatory transcription factors
such as the orphan nuclear receptor PXR are involved in
the induction of CYP3A4 and P-glycoprotein by, e.g.
rifampicin ([35] and references therein), it has been
speculated that the basal intestinal expression of these
proteins might be co-regulated. However, no significant
correlation was observed between enterocyte P-glyco-
protein and CYP3A4 levels in 25 kidney transplant
recipients [28], suggesting that the expression of CYP3A4
and P-glycoprotein in the intestine is regulated sepa-
rately. This does of course not preclude synergistic
Ó 2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 621–626
623
actions of CYP3A4 and P-glycoprotein during drug
absorption.
EVIDENCE OF SYNERGISTIC ACTIONS
OF CYP3A4 AND P-GLYCOPROTEIN
IN LIMITING ORAL DRUG
BIOAVAILABILITY
The available direct experimental evidence in support of
the concept that CYP3A4 and P-glycoprotein may act in
concert to limit oral drug bioavailability originates from
a limited number of in vitro and animal studies.
Obviously, it is a very difficult if not impossible task to
demonstrate in vivo in humans that the function of
CYP3A4 and P-glycoprotein in enterocytes is comple-
mentary. Moreover, factors such as level of expression of
these proteins along the length of intestine and satura-
tion phenomena due to high local drug concentrations
are likely to modulate the effect of P-glycoprotein on
intestinal, CYP3A4-mediated drug metabolism in vivo
[22,27].
Cummins et al. [36] recently set out to determine the
contribution of P-glycoprotein in determining the extent
of CYP3A4-dependent drug metabolism in CYP3A4-
transfected Caco-2 monolayers expressing both CYP3A4
and P-glycoprotein, using reasonably selective CYP3A4/
P-glycoprotein substrates and inhibitors. It was discov-
ered that when P-glycoprotein alone was inhibited (by
GG918), the extent of metabolism of the dual CYP3A4
and P-glycoprotein substrate K77 (a cysteine protease
inhibitor) was decreased, but there was no change in the
extent of metabolism for the exclusive CYP3A4 substrate
felodipine. The authors concluded that P-glycoprotein
can work in concert with CYP3A4 to increase the extent
of drug metabolism, by controlling the access of the drug
to the intracellular metabolizing enzyme [36]. It should
be noted that use of Caco-2 cells to investigate the
interplay between CYP3A4 and P-glycoprotein may be
problematic because expression of multiple drug efflux
transporters and low CYP3A4 content. There are also
other studies that have involved in vitro intestinal
models and lend support to the interplay hypothesis
[9,10,37,38]. In addition, support for this theory has
been obtained from a simulation model [39].
On the contrary, using CYP3A4-expressing Caco-2
cell monolayers, Mouly et al. [40] recently showed that
the P-glycoprotein inhibitor LY335979 increased the
formation rate of a major CYP3A4-mediated metabolite
(M7) of saquinavir at each saquinavir concentration
tested. The authors suggested that this might have
624
resulted from increased cellular content of saquinavir
due to reduced P-glycoprotein-mediated efflux. However,
interpretation of this finding is not straightforward as M7
is a P-glycoprotein substrate and is subject to secondary
and tertiary metabolism by CYP3A4 ([40] and references
therein). In any event, this study suggests that both
CYP3A4 and P-glycoprotein are involved in the intesti-
nal first-pass extraction of saquinavir.
Cummins et al. [41] later extended the findings from
their in vitro study by investigating modulation of
intestinal CYP3A4-mediated metabolism by P-glyco-
protein in vivo, using an isolated rat single-pass intes-
tinal perfusion system with mesenteric cannulation. K77
and GG918 were again used as a CYP3A4/P-glycopro-
tein substrate and P-glycoprotein inhibitor, respectively,
and midazolam was used as an exclusive CYP3A4
substrate. The results further supported a role for
P-glycoprotein in modulating the extent of intestinal,
CYP3A4-mediated biotransformation [41].
A number of in vitro studies and in vivo rat studies
performed to characterize the role of intestinal P-glyco-
protein in drug absorption and metabolism have relied
on substrates and inhibitors that affect both CYP3A4
and P-glycoprotein, precluding differentiation of the
relative contribution of CYP3A4 and P-glycoprotein on
intestinal drug metabolism.
There is at least one study performed in humans that
indirectly supports the interplay between P-glycoprotein
and CYP3A4 in the gut wall [42]. This study, in which
the small intestine was perfused with quinidine by means
of a multiluminal perfusion catheter in eight healthy
volunteers, demonstrated the importance of intestinal
P-glycoprotein and CYP3A4 for the plasma concentra-
tions of quinidine, a substrate of both P-glycoprotein and
CYP3A4. The dose-corrected plasma quinidine AUC from
zero to 3 h was negatively correlated with both intestinal
P-glycoprotein content and intestinal CYP3A4 content.
That is, higher amounts of these proteins were associated
with lower plasma quinidine concentrations, indicating
that the oral bioavailability of quinidine was limited by
both P-glycoprotein-mediated efflux and CYP3A4-
mediated metabolism in the gut wall. In addition, as
expected, dose-corrected intraluminal quinidine concen-
trations were positively correlated with intestinal
P-glycoprotein expression [42].
It deserves to be mentioned in this context that
interplay between CYP3A4 and P-glycoprotein may
also occur in the liver, as recently demonstrated by
Lau et al. [43]. They used an isolated perfused rat liver
model and found a significant increase in hepatic
Ó 2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 621–626
K. T. Kivistö et al.
digoxin metabolism (digoxin is metabolized by CYP3A
in the rat) in animals treated with quinidine, a potent
P-glycoprotein inhibitor, compared with the control
group. The authors hypothesized that quinidine
increased the extent of digoxin metabolism by blocking
the P-glycoprotein-mediated biliary secretion of digoxin
and thus prolonging exposure of digoxin to hepatic
CYP3A.
CONCLUSIONS
Although the hypothesis that CYP3A4 and P-glyco-
protein work together to coordinate an absorption
barrier against xenobiotics is attractive from a theoret-
ical point of view (Figure 1), support for this notion
largely comes from a small number of in vitro and
animal studies. Direct evidence to support synergism
between these two proteins remains elusive, and the
quantitative contribution of P-glycoprotein to the intes-
tinal absorption and CYP3A4-mediated metabolism of
Drug
Gut lumen Drug metabolite
Apical
(luminal)
ATP P-glycoprotein
4
A
Enterocyte
P3
Y
C
Basal
Figure 1 A scheme of the proposed functional interaction between
CYP3A4 and P-glycoprotein in human enterocytes. (1) Drug
absorption via passive diffusion or carrier-mediated processes
from the lumen of the gastrointestinal tract into the enterocyte.
(2) CYP3A4-mediated metabolism. (3) Transport of the parent drug
and/or its metabolite(s) from the enterocyte into the gut lumen
by P-glycoprotein. (4) Translocation of the drug and/or its
metabolite(s) across the basal membrane of enterocytes via passive
diffusion or carrier-mediated processes into the portal vein.
Reproduced from Ref. [26] with the permission of Blackwell
Publishing (Oxford, UK).
CYP3A4 and P-glycoprotein
xenobiotics in vivo is not clear. Possible synergism
between CYP3A4 and P-glycoprotein does not seem to
extend to the level of regulation, as there is evidence to
suggest that these proteins are not co-ordinately regu-
lated in the intestine. The functional interaction of
intestinal CYP3A4 and P-glycoprotein clearly warrants
further study. The ensuing knowledge would not only
help to better understand the absorption process of orally
administered drugs but would also be potentially useful
during drug development to solve problems related to
low bioavailability of new drug entities. Finally, apart
from CYP3A4 and P-glycoprotein, other proteins such as
UDP-glucuronosyltransferases (UGTs) and MDR-associ-
ated protein 2 (MRP2) may also act in concert to
facilitate detoxification of xenobiotics.
ACKNOWLEDGEMENTS
The authors’ work was supported by grants from the
Robert-Bosch Foundation (Stuttgart) and the Deutsche
Forschungsgemeinschaft (German Research Foundation,
Bonn) (FR 1298/2-3). M. Niemi is supported by a
fellowship from the Alexander von Humboldt Founda-
tion (Bonn, Germany).
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