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Department of Clinical Chemistry [H. A. B., W. J. N., O. v. T.] and Department of Medical Oncology [J. H. M. S.], the Netherlands Cancer Institute (Antoni van Leeuwenhoek Huis), 1066 CX Amsterdam, the Netherlands; Department of Pharmacy and Pharmacology, Slotervaart Hospital/the Netherlands Cancer Institute, 1066 EC Amsterdam, the Netherlands [J. H. B., H. R.]; and Glaxo Wellcome, Research Triangle Park, North Carolina 27709 [K. R. B.]
ABSTRACT
Previous studies in mice with disrupted mdr1a P-glycoprotein genes have shown that the oral bioavailability of paclitaxel is very low because of the presence of this drug-transporting protein in the intestinal wall. Additional studies with cyclosporin A have shown that this P-glycoprotein-inhibiting agent is able to increase the bioavailability of paclitaxel in mouse models and in patients. However, the potential immune-suppressive side effects of cyclosporin A renders this compound less suitable for chronic use in cancer patients. In this paper we present the results obtained with GF120918, an experimental P-glycoprotein inhibitor, on the oral bioavailability of paclitaxel in both wild-type and mdr1ab knockout mice. GF120918 (25 mg/kg) was administered p.o. by gavage 15 min or 2 h before oral or i.v. dosing of paclitaxel, respectively. Paclitaxel plasma levels were quantified by high-performance liquid chromatography. GF120918 increased the plasma values for areas under the concentration-time curve of oral paclitaxel in wild-type mice by 6.6-fold from 408 to 2701 ng·ml-1·h. Calculated relative to their respective values for area under the concentration-time curve after i.v. administration, GF120918 increased the oral bioavailability of paclitaxel in wild-type mice from 8.5 to 40.2%. The plasma pharmacokinetics of paclitaxel in mdr1ab knockout mice was not altered by GF120918, whereas the pharmacokinetics of paclitaxel in wild-type mice receiving GF120918 became comparable with mdr1ab knockout mice. This result indicates that GF120918 at this dose-level selectively and completely blocks P-glycoprotein in the intestines and does not notably interfere in the elimination of paclitaxel by metabolism or other transporters. On the basis of this result, GF120918 has been selected for additional study in humans.
INTRODUCTION
Paclitaxel (Taxol®, Paxene) has become an established drug in the treatment of various human malignancies (see reviews by Huizing et al., Ref. 1 , and Rowinsky and Donehower, Ref. 2 ). In current clinical practice, the drug is administered by i.v. infusion. Because of its very limited aqueous solubility, the drug is formulated at 6 mg/ml in a mixture of Cremophor EL and ethanol (1:1; v/v). Thus, patients who receive paclitaxel concomitantly receive substantial amounts of Cremophor EL, resulting in plasma levels of Cremophor EL of about 1% of the plasma volume (3) . The excipient Cremophor EL is believed to play a role in the (severe) hypersensitivity reactions occasionally observed in patients while on paclitaxel therapy (4 , 5) . Moreover, Cremophor EL also causes the nonlinear pharmacokinetic behavior of paclitaxel (6, 7, 8) .
In addition to avoiding the systemic effects of Cremophor EL, the
availability of an oral drug formulation would offer several additional
advantages over i.v. dosing, including patients’ preferences for oral
administration, elimination of the need for frequent visits to
the outpatient clinic, and easier chronic administration.
Initially, the oral route was thought to be impractical because of very
low bioavailability in preclinical studies (9)
. Additional
studies in mdr1a P-glycoprotein knock-out mice revealed that
this drug efflux pump is the major limiting factor in drug uptake from
the intestines because the plasma
AUC2
after oral
dosing was 6-fold higher in these mice than in wild-type controls
(10)
. Because the clearance of paclitaxel in knockout mice
was almost 2-fold lower, the oral bioavailability
(AUCoral/AUCi.v.·100%)
increased by 3.5-fold (from 11 to 35%). In the absence of
P-glycoprotein, first-pass metabolism [e.g., by cytochrome
P450 isoenzymes to 3-phydroxy-paclitaxel and
6
-hydroxy-paclitaxel (11, 12, 13)
] becomes an important
factor limiting the oral bioavailability of paclitaxel. This is
illustrated by the observation that the fraction of unchanged
paclitaxel recovered from the feces was reduced from 86% of the dose
in wild-type mice to <2% in knockout mice (10)
. Thus,
despite the virtually complete absorption from the gastro-intestinal
tract, the bioavailability in the knockout mice does not approach
100%. The plasma levels of the hydroxylated metabolites remained below
the limit of detection, whereas their contribution in the fecal
excretion was high [25–30% of the administered paclitaxel dose
(10)
]. Apparently, these metabolites are efficiently
excreted into the bile after their formation and do not reach the
systemic circulation.
A subsequent study with PSC833, a cyclosporin D analogue and potent P-glycoprotein-blocker, demonstrated the potential of using P-glycoprotein-blockers to increase paclitaxel plasma levels after oral administration (14) . The plasma AUC using the PSC833-paclitaxel combination was even higher than that achieved in mdr1a knockout mice receiving paclitaxel as a single agent, suggesting that the gain in systemic drug levels was also attributable to the inhibition of other drug-elimination pathways (metabolic enzymes or other transporters). Although not as potent as PSC833, cyclosporin A is a registered drug and is thus more readily available for clinical studies. After showing the usefulness of cyclosporin A in a preclinical setting (15) a subsequent clinical study demonstrated the potential usefulness of this approach in humans (16 , 17) . However, the use of cyclosporin A for long-term oral dosing may be hindered by the immune suppressive effect of this agent. Consequently, we are currently exploring other agents that block P-glycoprotein for increasing the oral bioavailability of paclitaxel.
Several other P-glycoprotein-blockers are under development [e.g., GF120918 (18 , 19) , LY335979 (20 , 21) , XR9576 (22) , and VX710 (23 , 24) ], however, primarily with the purpose to improve the treatment of P-glycoprotein-expressing multidrug resistant tumors. GF120918 is an acridonecarboxamide-derivative and has been shown to be a potent blocker of P-glycoprotein in tumor cells in vitro and in vivo (18) . This paper describes a study with GF120918 to enhance the oral bioavailability of paclitaxel in wild-type mice. The current studies have also included the use of mice carrying a disruption of both murine isoforms (mdr1a and mdr1b) of drug transporting P-glycoproteins (mdr1ab knockout mice; Ref. 25 ), which have recently become available in a 99% pure FVB background. By integration of groups of both wild-type and mdr1ab knockout mice receiving oral or i.v. paclitaxel, with or without GF120918, insight is obtained into both the potency as well as the selectivity for P-glycoprotein-inhibition of this agent.
MATERIALS AND METHODS
Animals.
Female wild-type FVB mice and 99% pure FVB mdr1ab knockout
mice, 9–14 weeks of age, were used throughout the experiments. Mice
were allowed to take water and food ad libitum.
Their body weights ranged from 18.7 to 28.4 g, and were evenly distributed throughout the different test groups. Animals were maintained and handled in accordance with institutional guidelines based on Dutch law.
Drugs.
Taxol® (paclitaxel 6 mg/ml, formulated in Cremophor EL:ethanol 1:1;
v/v) was obtained from Bristol Myers Squibb (Princeton, NJ).
Paclitaxel, pure compound, originated from Sankyo (Tokyo, Japan).
GF120918A (HCl salt) was obtained from Glaxo Wellcome (Research
Triangle Park, NC).
Dosing Solutions.
Paclitaxel solutions for oral drug administration were prepared by a
6-fold dilution of the pharmaceutical formulation with saline
(Braun Emmer Compascuum, The Netherlands). The final
concentration was 1 mg/ml. To circumvent the Cremophor EL-caused
nonlinear pharmacokinetic behavior of paclitaxel (6)
, the
stock solution of paclitaxel for i.v. dosing was prepared by dissolving
30 mg of pure compound in 2.5 ml of ethanol (Merck, Darmstadt, Germany)
and 2.5 ml of polysorbate 80 (Sigma, St. Louis, MO). This stock
solution containing 6 mg/ml of paclitaxel was stable for at least 1
year if stored at 4°C. Before injection, this stock solution was
diluted 6-fold with saline to a final concentration of 1 mg/ml and used
within 4 h.
GF120918 suspensions were freshly prepared the day before each experiment. A portion of 40 mg of GF120918A was accurately weighed and transferred into a glass tube. The powder was suspended in 7.5 ml of water for injection (NPBI) and transferred into a polypropylene Falcon tube (Becton Dickinson Labware, Franklin Lakes, NJ) containing 7.5 ml of concentrated stock vehicle (10 g/liter of hydroxypropyl methyl cellulose (100 centipoises; Sigma) and 2% Tween 80 (Sigma) in water (NPBI). The suspension was mixed for 10 min, and then further dispersed using a Polytron PT1200 homogenizer for 2 min. The suspension was kept protected from light and was stirred continuously. The final concentration was 2.75 mg/ml of GF120918A (salt) corresponding to 2.5 mg/ml of GF120918 (active substance).
The vehicle solution of GF120918 consisted of the concentrated stock vehicle diluted 1:1 (v/v) with water.
Administration Routes.
Oral drug or vehicle administrations were given by gavage. i.v. drug
administrations were done by injection with a 29-gauge needle into a
lateral tail vein using 300-µl syringes. Animals were placed under a
heating lamp prior to i.v. drug administration. No anesthetics were
used during these procedures.
Test Groups.
Eight different test groups, four groups of wild-type mice (A–D) and
four groups of mdr1ab knockout mice (E–H) were included in
this study. Groups A and E received GF120918 vehicle p.o. and oral
paclitaxel within 10–20 min. Groups B and F received GF120918 p.o. and
oral paclitaxel within 10–20 min. Groups C and G received GF120918
vehicle p.o. and i.v. paclitaxel after 2 h (±15 min). Groups D
and H received GF120918 p.o. and i.v. paclitaxel after 2 h (±15
min).
The dose level of paclitaxel was 10 mg/kg in all groups. The dose level of GF120918 was 25 mg/kg. Groups receiving oral paclitaxel consisted of at least six animals/time point, whereas at least three animals/time point were used when paclitaxel was administered i.v.
Blood sampling was performed at the following approximate time points after the administration of paclitaxel (in parentheses, for knockout mice only): groups A and E, 0.5, 1, 2, 3, 4, 6, and 8, (10 , 12 , and 16) h; groups B and F, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16, (24) h; groups C and G, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12, (16 and 24) h; and groups D and H, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, and 24 h.
Sample Collection and Handling.
Blood was obtained by cardiac puncture under anesthesia with
methoxyflurane. Potassium EDTA was used as an anticoagulant and the
plasma obtained after centrifugation (5 min, 3000 x g) was stored
at -20°C until analysis.
Analytical Methods.
Mouse plasma samples were diluted with blank human plasma. Paclitaxel
was determined using a validated high-performance liquid
chromatography-UV detection method (26)
. The lower
limit of quantitation using 200 µl of mouse plasma was 25 ng/ml.
The plasma levels of GF120918 have been analyzed using a newly developed assay.3 This assay is based on high-performance liquid chromatography with fluorescence detection after liquid-liquid extraction with tert-Butyl methyl ether. The lower limit of quantitation is 22.4 ng/ml using 50 µl of mouse plasma.
Pharmacokinetic Calculations.
Pharmacokinetic parameters were calculated by noncompartmental methods
using the software package Quattro Pro (Corel Corp., 1996; version
6.02). The plasma AUC from time 0 to the last sampling
point was calculated by the linear trapezoidal rule with the formula:
 |
with 
timen = 0.
The SE of the AUC was calculated with the law of propagation of
errors using the formula:
 |
The two-sided Student t test was used for statistical analyses.
RESULTS
Consistent with previous results the plasma levels of paclitaxel
in wild-type mice receiving the drug by the oral route remained very
low (Fig. 1)
. The plasma levels hardly
exceeded the 0.1 µM (
85 ng/ml) level, which is
considered of therapeutic relevance (27)
. The plasma AUC
of paclitaxel, however, increased significantly by 6.6-fold
(P < 0.001; Table 1
)
when GF120918 was given p.o. 10–20 min before the oral administration
of paclitaxel. The Cmax increased to 770 ±
120 ng/ml, and the plasma concentration remained above 85 ng/ml level
for >6 h. The administration of GF120918 also increased the plasma AUC
of paclitaxel when this drug was given i.v. to wild-type mice, but only
by a factor 1.4 (P < 0.01). This increased AUC
was attributable to a less-rapid decline of the plasma concentration.
The Cmax of i.v.-administered paclitaxel was
similar with or without GF120918, suggesting that this
P-glycoprotein-blocker does not affect the central distribution volume
of paclitaxel. However, the plasma concentration time curves started to
diverge after 1 h and were 
2-fold higher 2 h after the
administration of paclitaxel. The terminal half-life was
2-fold longer in the mdr1ab knockout mice relative to
wild-type controls. Taking into account this effect of GF120918 on the
Cl of paclitaxel, GF120918 very significantly increased the
oral bioavailability of paclitaxel in wild-type mice from 8.5% to
40.2% (P < 0.001).
|
|
The maximum plasma level of GF120918 ranged between 150 and 250 ng/ml and was reached at 2 h after oral administration. These levels were consistent with previous reports in mice (18) .
DISCUSSION
This study shows that GF120918 is able to increase the oral bioavailability of paclitaxel in mice significantly. The plasma AUC of paclitaxel achieved in wild-type mice when given with GF120918 became comparable with that in knockout mice. Moreover, mdr1ab knockout mice, which lack both murine isoforms of drug transporting P-glycoproteins, provide an elegant in vivo test system to monitor the selectivity of P-glycoprotein inhibitors on the pharmacokinetics of substrate drugs. Apparently, next to the inhibition of P-glycoprotein, GF120918 does not notably interact with other pathways involved in paclitaxel uptake or elimination. After both oral and i.v. paclitaxel administration, GF120918 did not change the course of the plasma concentration versus time curves of paclitaxel in knockout mice.
The results with GF120918 contrast with previous studies in mice using the P-glycoprotein-blockers cyclosporin A or PSC833 (14 , 15) . Although the interaction of these P-glycoprotein inhibitors have not been tested in knockout mice, the AUC of paclitaxel given in combination with oral cyclosporin A or PSC833 to wild-type mice was 2- to 5-fold higher than the AUC in knockout mice receiving paclitaxel alone. Consequently, when given p.o., the gain in the plasma AUC of paclitaxel with these cyclosporin analogues resulted for a substantial part from decreased metabolic elimination [e.g., by CYP450–3A4 (12 , 13 , 28) ] and/or by blocking other transporters of paclitaxel. The absence of an interaction with the pharmacokinetics of paclitaxel in knockout mice does not imply that GF120918 is unable to inhibit other transporters or enzymes. In fact, it has recently been shown that this compound can also block the ABC half-transporter Breast Cancer Resistance Protein (29 , 30) ; however, this goes without consequences because paclitaxel is not substrate of this transporter.
We have shown previously that a disruption of the mdr1a and mdr1b P-glycoprotein genes in mice does not affect hepato-biliary excretion of paclitaxel (25) . Apparently, other transporters in the biliary canalicular membrane compensate for the absence of drug transporting P-glycoproteins. This result is different from doxorubicin, which was much less excreted in the bile of mdr1a knockout mice (31) . In line with this result, a functional blockade of P-glycoprotein by GF120918 also resulted in a significant reduction of doxorubicin in an isolated perfused rat liver model (32) .
The difference in the plasma pharmacokinetics of paclitaxel between wild-type and mdr1ab knockout mice is mainly caused by the activity of P-glycoprotein in the gut wall, which is of mdr1a type. The direct excretion of paclitaxel from the blood, via the intestinal epithelium into the gut lumen, is markedly decreased in mdr1a (and mdr1ab) knockout mice relative to wild-type controls (10 , 25) . Conversely, (re)uptake of paclitaxel from the gut lumen (after biliary excretion or oral administration) into the systemic circulation is very effective in knockout mice, because the fecal excretion of unchanged drug amounts to only 2% of the dose (10) . The finding that the plasma concentration of paclitaxel in wild-type mice receiving GF120918 remains similar to that found in mdr1ab knockout mice for at least 12 h after i.v. administration of paclitaxel suggests that GF120918 blocks P-glycoprotein in the intestines during this entire period.
GF120918 is a very poorly water soluble compound for which no suitable i.v. formulation has become available. The oral formulation used throughout this study is a finely dispersed suspension. Clinical studies with GF120918 aimed to investigate its potential as a reversal agent in the treatment of multidrug-resistant tumors have demonstrated substantial interpatient variability in the plasma levels of GF120918 (33) . The variable plasma levels of GF120918 after oral administration, which may be caused by its poor aqueous solubility, have led to a postponement in this part of the drug development program. However, for the purpose of using this compound to increase the oral bioavailability of paclitaxel, the variation in the plasma levels of GF120918 may not be a major obstacle. The local concentration of GF120918 in the intestinal lumen is probably much more important and was apparently high enough to completely block intestinal P-glycoprotein in mice. Because the rate of disappearance of the P-glycoprotein inhibitor from the gut may be relevant for the duration of blocking P-glycoprotein, it may be speculated that a gradual dissolution of GF120918 in the intestinal tract, such as a slow release formulation, could even be advantageous to increase the oral bioavailability of paclitaxel.
Intrinsic or acquired (multi)drug resistance remains an important problem in the chemotherapeutic treatment of cancer patients. P-glycoprotein-inhibitors like GF120918 have been developed by drug discovery programs aimed at finding agents that block P-glycoprotein in tumor tissues and, by that, reversing P-glycoprotein-mediated multidrug resistance. It is generally anticipated that, within the coming years, studies using these compounds in combination with anticancer drugs with a high affinity for P-glycoprotein will resolve the issue of whether P-glycoprotein is of clinical relevance in multidrug-resistant (solid) tumors and whether P-glycoprotein blockers contribute to an improvement in treatment response. However, our recently obtained insight into the pharmacological role of P-glycoprotein in normal tissues, which fulfills a barrier function [e.g., the gut lumen-blood barrier (6 , 34) , the blood-brain barrier (35 , 36) , and the blood-fetus barrier (37 , 38) ], makes this class of compounds potentially very useful when increased levels of P-glycoprotein substrate drugs at these sanctuary sites are required for therapeutic reasons. On the basis of the promising results with GF120918 in this study, a study in patients receiving the combination of oral GF120918 and oral paclitaxel has been initiated. These studies will determine whether the combination provides sufficiently high and reproducible plasma levels of paclitaxel to allow oral administration of this drug.
ACKNOWLEDGMENTS
The authors thank Ton Schrauwers for excellent biotechnical assistance.
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 To whom requests for reprints should be
addressed, at Department of Clinical Chemistry, the Netherlands Cancer
Institute (Antoni van Leeuwenhoek Huis), Plesmanlaan 121, 1066 CX
Amsterdam, the Netherlands. Phone: 31-20-512-2792; Fax: 31-20-617-2625;
E-mail: OTEL{at}nki.nl 
2 The abbreviations used are: AUC, area under the
concentration-time curve; Cl, clearance;
Cmax, maximum plasma level.
3 M. Kemper, B. Janson, K. R. Brouwer, J. H. M.
Schellers, J. H. Beÿnen, and O. van Tellingen. Bioanalysis and
preliminary pharmacokinetics of GF120g18 in plasma of mice and humans,
manuscript in preparation.
Received 6/16/00; revised 8/30/00; accepted 8/30/00.
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) or in
combination with GF120918 (
).