Clinical Cancer Research Vol. 6, 2598-2603, July 2000
© 2000 American Association for Cancer Research
Role of Intestinal P-glycoprotein in the Plasma and Fecal Disposition of Docetaxel in Humans1
Lia van Zuylen2,
Jaap Verweij,
Kees Nooter,
Eric Brouwer,
Gerrit Stoter and
Alex Sparreboom
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, 3008 AE Rotterdam, the Netherlands
 |
ABSTRACT
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|---|
Multidrug
resistance (MDR)-1-P-glycoprotein (P-gp) is a drug-transporting protein
that is abundantly present in biliary ductal cells and epithelial cells
lining the gastrointestinal tract. Here, we have determined the role of
P-gp in the metabolic disposition of the antineoplastic agent docetaxel
(Taxotere) in humans. Pharmacokinetic profiles were evaluated in five
cancer patients receiving treatment cycles with docetaxel alone (100
mg/m2 i.v. over a 1-h period) and in combination with a new
potent inhibitor of P-gp activity, R101933 (200–300 mg b.i.d.). The
terminal disposition half-life and total plasma clearance of docetaxel
were not altered by treatment with oral R101933 (P 
0.27). The cumulative fecal excretion of docetaxel, however, was
markedly reduced from 8.47 ± 2.14% (mean ± SD) of the dose
with the single agent to less than 0.5% in the presence of R101933
(P = 0.0016). Levels of the major cytochrome P450
3A4-mediated metabolites of docetaxel in feces were significantly
increased after combination treatment with R101933
(P = 0.010), indicating very prominent and
efficient detoxification of reabsorbed docetaxel into hydroxylated
compounds before reaching the systemic circulation. It is concluded
that intestinal P-gp plays a principal role in the fecal elimination of
docetaxel by modulating reabsorption of the drug after hepatobiliary
secretion. In addition, the results indicate that inhibition of P-gp
activity in normal tissues by effective modulators, and the
physiological and pharmacological consequences of this treatment,
cannot be predicted based on plasma drug monitoring alone.
|
Introduction
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Acquired or intrinsic resistance of malignant cells to taxanes and
other naturally occurring anticancer drugs has been linked to the so
called "classical" mechanism of
MDR,3
which can cause
decreased intracellular concentrations of these drugs (1)
.
This MDR phenotype is characterized by increased levels of P-gp, a
member of the ATP binding cassette superfamily of transmembrane
transport proteins with Mr
170,000 encoded by the MDR1 gene, which acts
as an energy-dependent drug-efflux pump with broad substrate
specificity (1)
. P-gp expression has been found in nearly
all of the tumor types, ranging from leukemia to carcinoma, and it has
also been reported in a number of normal tissues, mainly in specialized
epithelial cells with secretory functions including the apical biliary
surface of hepatocytes and epithelial cells of the intestinal tract
(2)
. The physiological functions of P-gp are still
speculative at this time, but possibilities include involvement in the
protection of epithelial mucosal cells in the gastrointestinal tract
from xenobiotics, in transport of steroids in the adrenals and bile
salts in the liver, in protein secretion in the kidneys
(3)
, and, most recently discovered, in migration of
dendritic cells and T-lymphocytes out of the skin (4)
. In
addition, the expression of P-gp in the capillary endothelial cells
forming the blood-brain and the blood-testis barrier apparently
protects these organs from exogenous toxins, and thus contributes to
the role of these anatomical sites as drug sanctuaries (reviewed in
Ref. 5
).
Several studies have shown that P-gp-mediated MDR is of clinical
significance, and this observation has stimulated a search for
noncytotoxic agents that can reverse this resistance phenomenon
(6
, 7)
. Clinical trials performed thus far with identified
P-gp inhibitors given in combination with anticancer drugs, however,
have raised important issues regarding the safety of the
chemotherapeutic treatment because of drug interactions that increased
or changed the spectrum of associated toxic side effects (8
, 9)
. The results of these clinical trials in combination with the
poorly defined pharmacological and physiological function of P-gp in
humans emphasize the need to perform studies to further evaluate the
role of P-gp in the disposition of substrate drugs. The importance of
these studies is further underscored by the previous use of anticancer
drugs that are rather poor substrates of P-gp given with nonspecific
inhibitors of P-gp (9)
. Thus, in the present study, we
evaluated the role of P-gp in the plasma disposition and fecal
elimination pathways of docetaxel, one of the best known substrates of
P-gp (10)
, in humans using a combined treatment with the
new p.o. administered P-gp inhibitor R101933 as a model compound.
|
Materials and Methods
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Drug Administration.
Docetaxel (Rhône-Poulenc Rorer, Antony Cedex, France) was
supplied as a concentrated solution in polysorbate 80 (40 mg/ml;
Taxotere) and was administered to five cancer patients at a dose
of 100 mg/m2 as a 1-h i.v. infusion. Three weeks
later, the same dose was administered to each patient 1 h after
intake of R101933 on day 3. All of the patients received premedication
with dexamethasone (8 mg b.i.d.), starting 24 h prior to
infusion of docetaxel and continuing for 4 days thereafter.
R101933 (methyl
6,11-dihydro-11-(1-[2-[4-(2-quinolinyl-methoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate),
an agent acting as a specific antagonist of P-gp, was supplied by
Janssen Research Foundation (Beerse, Belgium) as an oral solution
containing 10 mg/ml of the active compound in 15%
hydroxypropyl-ß-cyclodextrin. The drug was administered p.o. twice
daily for 5 consecutive days (i.e., days 1–5) with 200 ml
of water, at least 1 h after a meal. The clinical protocol was
approved by the institutional ethics committee, and signed informed
consent was obtained from each participant before entering the study.
Sample Collection and Processing.
Blood specimens were acquired in all of the patients during both
treatment courses. Sample volumes of 
6 ml were drawn directly from a
peripheral venous access device into tubes containing lyophilized
sodium heparin as an anticoagulant. Blood samples were collected
immediately before infusion, and at 0.5, 1, 1.25, 1.5, 2, 3, 7, 11, 23,
and 31 h after the start of infusion. All of the samples were
centrifuged immediately for 10 min at 1000 x g to
yield plasma, which was stored frozen at -20°C in polypropylene
vials until the time of analysis.
Complete stool collections for docetaxel analysis were obtained for the
duration of the study (i.e., up to 31 h after the start
of drug administration). This space of time was chosen based on
previous fecal excretion studies with the structural related
agent paclitaxel (11)
. Fecal specimens were collected in
polystyrene containers and stored immediately at -20°C. Weighted
feces samples were homogenized individually in 3 volumes of a phosphate
buffer [containing 0.01 M potassium phosphate,
0.137 M sodium chloride and 2.7
mM potassium chloride in the presence of 0.05%
(w/v) glucose (pH 7.4)] using five 1-min bursts of an Ultra-Turrax T25
homogenizer (IKA-Labortechnik, Dottingen, Germany) operating at 20,500
rpm. Aliquots of 500 µl of feces homogenates were diluted with human
plasma (1:1, v/v) and stored frozen at -80°C prior to further
processing.
Analytical Methods.
A pure reference standard of docetaxel (batch: 14PROC9230; purity:
98.0% by HPLC) was kindly supplied by Rhône-Poulenc Rorer, and
was used as received. Plasma concentrations of docetaxel were
determined by a validated HPLC assay with mass-spectrometric detection,
with a lowest limit of quantitation of 1 ng/ml. Samples (200 µl) were
pretreated by solid-phase extraction using end-capped Bond Elut nitrile
microcolumns (Varian, Harbor City, CA). A stainless steel analytical
column (100 x 4.6 mm, internal diameter) packed with 3 µm of
Hypersil BDS C18 material (Alltech, Breda, the Netherlands) was
used for chromatographic separation, and gradient elution was performed
with a mixture of acetonitrile and 0.02 M ammonium acetate
(pH 4.0) at a flow rate of 0.8 ml/min. Paclitaxel (Bristol-Myers
Squibb, Wallingford, CT) was used as internal standard.
Authentic reference standards of the docetaxel metabolites M1, M2, M3,
and M4 (Fig. 1)
were obtained after
isolation and purification of a patient fecal sample, as described
previously (12)
, and their concentrations in feces
homogenates were determined by reversed-phase HPLC with UV detection
using a modification of a procedure described elsewhere
(13)
. In brief, quantitative extraction was achieved by a
single solvent extraction of 0.5-ml samples with a mixture of
acetonitrile-n-butyl chloride (1:4, v/v). Chromatography was
performed at 60°C using an Inertsil ODS-80A column (150 x 4.6
mm; 5-µm particle size; GL Science, Tokyo, Japan) protected by a
Lichrospher 100 RP-18 end-capped-guard column (4.0 x 4.0 mm;
5-µm particle size; Merck, Darmstadt, Germany), and a 1-h exponential
gradient elution (45–75%; 1 ml/min) of methanol in
water-tetrahydrofuran-aqueous ammonium hydroxide (97.4:2.5:0.1, v/v/v)
at pH 6.0. The column effluent was monitored at a wavelength of 230 nm.
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Fig. 1. Chemical structures of docetaxel
(A) and its major cytochrome P450 3A4-mediated
metabolite M4 (B).
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|
Concentrations of R101933 and its esterase-mediated carboxylic acid
metabolite, R102207, were determined by a validated HPLC method
involving solid-phase extraction on Bond-Elut Certify microcolumns
(Varian). Standard curves were prepared in drug-free human
plasma and were expanded to encompass concentrations between 2 and
10,000 ng/ml A 1-ml aliquot of standard or plasma sample was mixed with
3 ml of 1 M aqueous acetic acid and 100 µl of internal
standard solution (R125026 in acetonitrile at 10 µg/ml). Before
loading, columns were preconditioned with 3 ml of ethanol, 3 ml of
water, and 1 ml of 1 M of aqueous acetic acid. Consecutive
washing steps involved 3 ml of water, 1 ml of aqueous acetic acid, and
3 ml of ethanol, and elution was performed with 3 ml of a mixture of
ethanol-ammonia (98:2, v/v). Samples were dried under nitrogen
at 65°C and redissolved in 100 µl of 0.02 M ammonium
formate (pH 4.0)-acetonitrile-ethanol (50:25:25, v/v/v). Chromatography
was performed on a column (100 x 4.6 mm) packed with 3-µm
Hypersil BDS C8 material (Alltech), and gradient elution (0.8 ml/min)
with a mixture of 0.02 M ammonium formate (pH 4.0),
acetonitrile, and ethanol. UV absorption measurements were performed at
a wavelength of 270 nm. Determination of analyte concentrations was
based on log-transformed peak areas of R101933 and R102207 and the
internal standard versus nominal concentrations by
interpolation using linear regression analysis.
Pharmacokinetic Analysis.
Individual plasma concentration-time curves of docetaxel were analyzed
by a twocompartmental model using the software package WinNonlin
(Pharsight, Mountain View, CA). All of the curves were fitted using the
actual infusion duration and blood sampling times. Pharmacokinetic
parameters were calculated by standard methods. To test parameter
differences for statistical significance among treatment courses, a
two-tailed paired Student’s t test was performed.
P values of less than 0.05 were considered statistically
significant.
In Vitro Studies.
A functional in vitro study was performed to evaluate
whether oral R101933 in humans yields plasma levels that are capable of
inhibiting P-gp function in tumor cells. The parental human ovarian
carcinoma cell line A2780 (P-gp-negative) and the derived
anthracycline-resistant lines A2780T100 and
2780AD (both P-gp-positive), developed by transfection of P-gp and
step-wise exposure to doxorubicin, respectively, were grown and
maintained in colorless RPMI 1640 (Brunschwig, Amsterdam, the
Netherlands). Cells were kept in continuous logarithmic growth at
37°C in a humidified atmosphere in 5% CO2/95%
air in medium supplemented with 10% (w/v) heat-inactivated bovine calf
serum (Hyclone, Logan, UT), penicillin, streptomycin, and
L-glutamine. Exponentially grown cells were
trypsinized, packed by centrifugation for 5 min at 1500 x
g, and washed twice with medium. The cells were counted
microscopically and transferred to protein-free RPMI to dilutions
containing 4.0 x 105 cells per ml.
Inhibition of P-gp-mediated drug efflux in each of the cell lines was
evaluated using a daunorubicin (final concentration, 1 µg/ml)
retention assay, in the presence of various concentrations of R101933,
ranging from 1 to 1000 ng/ml. Preliminary time course experiments
revealed that at a given R101933 concentration, daunorubicin uptake in
the cells did not change after 90 min, at which time equilibrium was
reached. Thus experiments were carried out with a 2-h incubation period
at 37°C, using 0.5-ml aliquots of the cell suspension in 4.5-ml
polypropylene screw-cap tubes (Greiner, Alphen aan den Rijn, the
Netherlands). The addition of R101933 was done after extraction of the
compound from a human plasma matrix or patient sample using a mixture
of acetonitrile and n-butyl chloride (1:4, v/v), and
reconstitution of dried extracts in neat medium by agitation. During
the incubation period, tubes were gently vortex-mixed at 30-min
intervals to prevent clogging of the cells. Intracellular levels of
daunorubicin were measured using flow cytometry with the aid of a
fluorescence-activated cell sorter. The fluorescence intensity in the
resistant cell lines relative to that observed in the A2780 parental
cell line in the absence of R101933, expressed as percentage, was
plotted relative to the R101933 concentration.
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Results
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Plasma Pharmacokinetics.
The results of paired plasma concentration-time profiles of
unchanged docetaxel given with and without cotreatment of oral R101933
were remarkable similar for all of the patients studied (Fig. 2)
. The mean pharmacokinetic parameters
of docetaxel for both treatment courses are summarized in Table 1
. There were no statistically
significant differences in any of the studied docetaxel kinetic
parameters, including the AUC and terminal disposition half-life, which
suggested that R101933 did not influence the disposition of the taxane
in the systemic circulation. The observed peak plasma concentrations of
R101933 were in the range of 25.3–168 ng/ml and 83.1–142 ng/ml in the
absence and presence of docetaxel, respectively. Concentrations of
R101933 in this range were observed to inhibit P-gp-mediated
daunorubicin efflux in two cell lines with known expression of P-gp and
resistance to anthracyclines (Fig. 3)
. In
all of the patients, there was extensive formation of the
pharmacologically inactive compound, R102207, resulting from an ester
hydrolysis, with peak levels approximately 75-fold higher (range,
33–124) than that of the parent drug.
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Fig. 2. Plasma concentration versus time
profiles of docetaxel in five patients treated with docetaxel alone
( ;100 mg/m2 as a 1-h i.v. infusion) or in combination
with oral R101933 (•; 200 or 300 mg b.i.d.). Data are presented as
mean values (symbols) ± SD (error
bars).
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Fecal Elimination.
In humans, excretion of docetaxel via the feces is a major route
of drug elimination (12
, 14)
. To evaluate the effects of
P-gp inhibition on elimination pathways of docetaxel, feces samples
were collected over a period of 31 h from all five of the patients
during both treatment courses with and without R101933. Preliminary
insight obtained from work of our laboratory into the composition of
docetaxel metabolites present in feces samples indicated that apart
from docetaxel, seven chromatographic peaks absorbed at 230 nm, the
peak wavelength of taxane derivatives. Structural identification using
HPLC and off-line mass spectrometry showed that the major peak was M4,
a known metabolite of docetaxel resulting from hydroxylation reactions
on the tert-butyl propionate side chain (15)
.
Using reference standards, three of the minor peaks were identified as
metabolites resulting from oxidation of one of the methyl groups on the
tert-butyl propionate side chain (M2), and spontaneous
cyclization of this alcohol derivative to the two diastereoisomers M1
and M3.
In patients treated with docetaxel alone, 8.47 ± 2.14%
(mean ± SD; n = 5) of the administered dose was
excreted in the first 31 h as the parent drug, whereas 13.3 ± 1.81% of the dose could be accounted for by metabolite M4 (Table 1)
. The total fecal recovery of the metabolites M1, M2, and M3 was very
low in all of the patients (less than 0.5% of the dose; data not
shown) and apparently the compounds play only a minor role in the
overall drug disposition. In the same group of patients,
coadministration with R101933 resulted in markedly reduced fecal
excretion of unchanged drug to less than 0.5% of the administered dose
(P = 0.0016). In contrast, however, the excretion of
metabolite M4 was significantly increased in all of the patients to
20.1 ± 4.39% of the dose (P = 0.010). These data
clearly show that R101933 administered p.o. causes a profound
alteration of P-gp-mediated intestinal reabsorption of docetaxel,
without modifying the drug’s kinetic behavior in plasma.
|
Discussion
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In the present study we have shown that intestinal P-gp plays a
principal role in the fecal elimination pathways of docetaxel without
modifying the pharmacokinetic behavior of the drug in the systemic
circulation. Previous investigations have shown a major role of the
cytochrome P450 3A4 isozymes in docetaxel metabolism. In humans, the
principal biotransformation routes involve hydroxylation of the
tert-butoxy function in the C13 side chain, followed by a
spontaneous cyclization reaction (15)
. The four principal
metabolites resulting from this pathway have substantially less
cytotoxic activity on tumor and nonmalignant hematopoietic cells as
compared with the parent drug (12)
. Fecal excretion of
docetaxel and its metabolites has been previously reported in two other
cases (14
, 15)
, and in both, M4 was the main metabolite,
very similar to our present findings, and accounted for a larger
fraction of the recovered dose than docetaxel itself. Interestingly,
this metabolite can only be detected in the systemic circulation in
about 30% of the patients treated with docetaxel at a dose of 100
mg/m2 and reaches peak plasma levels ranging form
only 22 to 230 ng/ml (16)
. This makes it very likely that
metabolite M4 is very efficiently excreted through a biliary secretion
pathway into the intestinal lumen immediately after its formation, and
that reabsorption is low. In our patients, we observed that
coadministration with R101933 had a marked effect on the fecal
elimination of docetaxel, changing from excretion partly as unchanged
drug in case of single-agent administration to almost exclusively
through metabolic breakdown (mainly to M4) in the combination
treatment. The similarity of the terminal disposition phases in plasma
of docetaxel between treatment courses indicate that the reduced fecal
excretion of the parent drug in the patients receiving R101933 is
unlikely to be related to diminished (P-gp-mediated) biliary secretion.
This is also in line with recent preclinical studies performed in mice
lacking mdr1 (drug-transporting) P-gp, which indicates that these
proteins are not essential per se for normal hepatobiliary
secretion of the related compound, paclitaxel (17)
. After
biliary secretion of docetaxel given in combination with R101933,
reabsorption of drug from the intestinal lumen seems to be a very
efficient process. This does not, however, result in increased plasma
levels because of a virtually complete first-pass extraction and/or
docetaxel metabolism in the liver and intestinal mucosa, which also has
significant expression of cytochrome P450 3A isozymes (Ref.
9
; see Fig. 4
for a
schematic representation of the role of intestinal P-gp in docetaxel
metabolism and excretion). These findings lend further support to
previous observations that the absorption of substrate drugs from the
intestines can be increased by concomitant administration with P-gp
inhibitors (reviewed in Ref. 18
).
The present data also raise important questions regarding the role of
endogenously expressed P-gp (for instance in the bile canaliculi,
kidneys, and intestinal epithelial cells) in the pharmacokinetics of
substrate drugs in plasma. It has been shown previously that R101933
does not interfere with docetaxel metabolism in preclinical systems, it
does not induce cytochrome P450 isozymes, and the major metabolic
routes of the modulator itself is ester hydrolysis, which is
independent of cytochrome P450
activity.4
Our results of
unaltered plasma concentrations of docetaxel in the combination with
R101933 is consistent with the postulated concept that pharmacokinetic
interference between P-gp modulators and anticancer drugs is the result
of competition for (cytochrome P450) enzymes involved in drug
metabolism (8)
. This is also in keeping with previous
knowledge from data generated in P-gp knock-out mice (5
, 17, 18, 19)
and sheds light on some important mechanistic aspects of
drug-drug interactions. Most importantly, our data clearly indicate
that inhibiting P-gp function in normal tissues by administration of an
effective modulator, the physiological and pharmacological consequences
of this treatment cannot be predicted based on plasma drug measurement
alone.
Given the dominant pharmacological role of intestinal P-gp activity in
the efficiency and pattern of fecal excretion of docetaxel, we expect
that the possibility to inhibit its activity completely with a p.o.
administered P-gp modulator as demonstrated in this study can have
important pharmacological applications. One of these applications is to
increase the oral bioavailability of taxane drugs, which are known to
display poor absorption characteristics after oral drug administration
(19)
. Indeed, recent experimental data have shown that
coadministration of oral PSC833 or cyclosporin A (both substrates of
cytochrome P450 3A4 isozymes) increased the AUC for paclitaxel in mice
more than 10-fold (20)
, and preliminary findings from the
same group indicate that the same applies to paclitaxel administered to
cancer patients (21)
. On the basis of our present data,
which show a very prominent and efficient detoxification of reabsorbed
docetaxel into hydroxylated metabolites before it can reach the
systemic circulation, we expect that this approach of increasing drug
bioavailability is unlikely to succeed unless the modulator
significantly interferes with docetaxel metabolism.
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ACKNOWLEDGMENTS
|
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We thank Janssen Research Foundation (B-2340 Beerse, Belgium)
for providing R101933 and for the pharmacokinetic analysis of
docetaxel. We are grateful to Cornelis J. Bol for critical review of
the manuscript.
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FOOTNOTES
|
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Previously presented at the AACR-NCI-EORTC
meeting, held in Washington on November 16 to 19, 1999. 
2 To whom requests for reprints should be
addressed, at Department of Medical Oncology, Rotterdam Cancer
Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam,
P.O. Box 5201, 3008 AE Rotterdam, the Netherlands. Phone:
31-10-4391338; Fax: 31-10-4391003; E-mail: zuylen{at}onch.azr.nl
3 The abbreviations used are: MDR, multidrug
resistance; P-gp, MDR1 P-glycoprotein; M1 and M3,
diastereoisomers of
3'-de-tert-butoxycarbonylamino-3'-[3-(5,5-dimethyl-4-hydroxy-2-oxo-1,
3-oxazolidinyl)]-docetaxel; M2
(3'-de-tert-butoxycarbonyl-3'-2-(1-hydroxy-2-meth-yl)propyloxycarbonyl-docetaxel;
M4
(3'-de-tert-butoxycarbonylamino-3'[3-(5,5-di-methyl-2,4-dioxo-1,3-oxazolidinyl)]-docetaxel;
AUC, area under the concentration versus time
curve; HPLC, high-performance liquid chromatography.
4 G. Mannens, unpublished data (on file,
Janssen Research Foundation).
Received 12/23/99;
revised 4/10/00;
accepted 4/19/00.
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Hoosier Oncology Group Randomized Phase II Study of Docetaxel, Vinorelbine, and Estramustine in Combination in Hormone-Refractory Prostate Cancer with Pharmacogenetic Survival Analysis.
Clin. Cancer Res.,
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[Abstract]
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ABSTRACT
Introduction
) and 2780AD (
) relative to that observed
in the A2780 parental cell line (•) in the absence of R101933.
Experiments were carried out with a 2-h incubation period at 37°C
with R101933 present at various concentrations. Data points, expressed
as percentage, are mean values of at least three independent
experiments performed in duplicate; bars, SEs.
Gray box, the range of R101933 peak levels observed in
the five patients after treatment with a p.o. dose of 200 or 300 mg.
Over the entire drug concentration range, substantial increases in
intracellular fluorescence, induced by R101933-mediated inhibition of
P-glycoprotein activity, could be detected.
, model of the hepatic-cellular plate showing the bile
collecting system with hepatic metabolism of docetaxel from the
systemic circulation or the portal vein after reabsorption following
the biliary secretion by cytochrome P450 3A4 isozymes into metabolite
M4 and its subsequent secretion in the terminal bile duct. 
, model
of the intestinal epithelium showing reuptake of docetaxel into the
intestinal lumen, P-glycoprotein-mediated efflux of docetaxel and its
inhibition by R101933 and intestinal metabolism by the cytochrome P450
3A4 enzyme system. *, sites of drug measurement; Doc,
docetaxel; CYP3A4, enzymes of the cytochrome P450
family isoform 3A4.