[CANCER RESEARCH 56. 2112-2115,
May 1. 1996]
Nonlinear Pharmacokinetics of Paclitaxel in Mice Results from the Pharmaceutical
Vehicle Cremophor EL
Alex Sparreboom,1 Olaf van Tellingen, Willem J. Nooijen, and Jos H. Beijnen
Department of Clinical Chemistry; Antimi van Leeuwenhoek HuÃ-s,the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam ¡A.S., O. v. T., W. J. N.l. Department
>ifPharmacy. Slotenaart Hospital, Louwesweg 6, 1066 EC. Amsterdam ¡J.H. B.¡and Department of Analysis and Toxicology. Faculty of Pharmacy: Utrecht University: P.O. Box
80082. 3508 TB Utrecht ¡J.H. BJ. the Netherlands
ABSTRACT
Studies in humans and mice have demonstrated
a nonlinear pharma-
cokinetic behavior of paclitaxel. Because of its poor water solubility, the
drug is formulated in a mixture of Cremophor EL and ethanol (1:1, v/v;
Taxol). We hypothesized that the substantial amounts of concurrently
administered Cremophor EL could have a major influence on the pharmacokinetic behavior of paclitaxel. To determine the effect of the phar
maceutical vehicle Cremophor EL on the disposition of paclitaxel, female
FVB mice received paclitaxel by i.v. injection at dose levels of 2, 10, and
20 mg/kg by appropriate (standard) dilution of the commercially available
formulation of paclitaxel (Taxol) with saline. The drug was also given at
2 mg/kg with supplemented Cremophor EL-ethanol to achieve the same
amount of vehicle as by standard administration of 10 mg/kg. Further
more, paclitaxel formulations in Tween 80-ethanol (1:1, v/v) and dimethylacetamide were tested. Plasma samples were collected between 5 min
and 48 h, and tissue specimens were sampled at 1, 4, and 8 h after drug
administration. Paclitaxel and metabolites were quantified by high-per
formance liquid chromatography. Cremophor EL levels were determined
by a novel high-performance liquid chromatography procedure. For com
parative reasons, Cremophor EL was also assayed in plasma samples from
three patients receiving a 3-h i.v. infusion of 175 mg/m2 of paclitaxel. A
marked nonlinear pharmacokinetic behavior of paclitaxel was observed
when the drug was formulated in Cremophor EL-ethanol. The clearance
of 2.37 L/h/kg at 2 mg/kg was reduced to 0.33 and 0.15 L/h/kg at 10 and
20 mg/kg, respectively. When 2 mg/kg were given with an amount of
Cremophor EL-ethanol matching that of the 10-mg/kg dose level, the
clearance was 0.56 L/h/kg. If administered at 10 mg/kg in Tween 80ethanol or at 2 and 10 mg/kg in dimethylacetamide, the clearances were
2.66, 2.57, and 2.62 L/h/kg, respectively. Despite the fact that much higher
plasma levels of paclitaxel are reached when given in the Cremophor
EL-ethanol formulation, the tissue levels were essentially similar with all
tested drug preparations. The Cremophor EL levels in patients were in the
same order of magnitude as those observed in mice after administration of
2 and 10 mg/kg. These data demonstrate that Cremophor EL has a
profound effect on the pharmacokinetics of paclitaxel in mice. Because
Cremophor EL levels in mice and humans are within the same range, it is
very likely that Cremophor EL also contributes substantially to the non
linear pharmacokinetic behavior of paclitaxel observed in humans.
INTRODUCTION
Paclitaxel is a natural product isolated from the Pacific yew tree,
Taxus brevifolia and is the lead compound of a class of new antitumor
drugs, which act by stabilizing microtubules (1). It has already be
come an important drug in the management of ovarian, breast, and
lung cancers (1). A substantial number of clinical pharmacokinetic
studies with paclitaxel have been performed to date and have shown
a nonlinear pharmacokinetic behavior (2-6). A more than propor
tional increase in the area under the AUC2 and the peak plasma level
Received 11/20/95; accepted 3/1/96.
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.
1To whom requests for reprints should be addressed. Phone: 31-20-5122792: Fax:
31-20-6172625.
•¿
The abbreviations used are: AUC. plasma concentration-time
curve; HPLC.
high-performance liquid chromatography; CI. apparent clearance.
(Cmax) with dosage suggest that both the elimination and the tissue
distribution are saturable processes (2-4). Complex mathematical
models have been developed, which appear to give a reasonable fit of
the paclitaxel AUCs (3, 4). However, the fundamental reasons for this
nonlinear pharmacokinetic behavior are still poorly understood. Pre
vious studies on drug disposition in mice have suggested that nonlin
ear pharmacokinetics also occurs in this species (7, 8).
Because of its poor water solubility, paclitaxel is currently formu
lated in a mixture of polyoxyethyleneglycerol triricinoleate 35 (Cre
mophor EL) and dehydrated ethanol USP (1:1, v/v). Before adminis
tration, it is diluted in 0.9% (w/v) sodium chloride or 5% (w/v)
dextrose to a final drug concentration ranging between 0.3 and 1.2
mg/ml (1). Considerable amounts of Cremophor EL are given con
currently with paclitaxel. In fact, the maximum dose of paclitaxel that
can be administered to mice by i.v. bolus injection (i.e., 20 mg/kg) is
dictated by the acute lethal toxicity of this vehicle (7). At this dose
level, a mouse of 24 g receives about 40 /xl of pure Cremophor EL.
Although humans receive relatively less Cremophor EL with paclitaxel
therapy (i.e., up to 25 ml of Cremophor EL at a dose level of 175 mg/m2
paclitaxel), the effects of Cremophor EL on the pharmacokinetics of
paclitaxel cannot be ruled out because there are no comparative data
available on the pharmacokinetics of this substance in mice and humans.
In the present study, we have investigated the pharmacokinetics of
paclitaxel at different dosages and drug formulations to determine the
effects of Cremophor EL on the disposition of paclitaxel. We also
present a comprehensive analysis of the pharmacokinetics of Cremo
phor EL in mice and preliminary results in humans by using a novel
analytical method based on HPLC.
MATERIALS
AND METHODS
Chemicals. Paclitaxel (solid; batch 80617492D), commercially available
paclitaxel formulated in Cremophor EL-dehydrated ethanol USP (1:1, v/v;
Taxol), and 2'-methylpaclitaxel were obtained from the Bristol-Myers Squibb
Co. (Princeton, NJ). Judged from reversed-phase HPLC, the purity of pacli
taxel and 2'-methylpaclitaxel was higher than 98.0%. Reference standards of
the paclitaxel metabolites 3'-p-hydroxypaclitaxel
(I), 6a-hydroxypaclitaxel
(II), and 6a,3'-/7-dihydroxypaclitaxel
(III) were isolated from patient feces
samples, as described in detail previously (9). Lyophilized BSA originated
from Organon Teknika BV (Boxtel, the Netherlands). Cremophor EL [specific
gravity (25°C/25°C)= 1.05-1.06; lot 32H0925] and margaric acid were
purchased from Sigma Chemical Co. (St. Louis, MO). All other chemicals
were of analytical or Lichrosolv gradient grade, and originated from E. Merck
(Darmstadt, Germany). Drug-free human plasma was obtained from the Cen
tral Laboratory of the Blood Transfusion Service (Amsterdam, the Nether
lands). Purified deionized water was prepared by the Milli-Q Plus system
(Waters Association, Milford, MA) and was used throughout.
Animals. Female FVB mice (ages 10-14 weeks) with a mean body weight
of 24 g were used in all experiments. The mice were handled and housed
according to institutional guidelines in a protected environment in conven
tional plastic cages and maintained on an automatic 12-h lighting cycle at a
temperature of 22-24°C. The animals were given a standard chow diet (Hope
Farms BV. Woerden. the Netherlands) and acidified water ad libitum.
Drug Formulations. Paclitaxel formulated in Cremophor EL-ethanol (1:1,
v/v) was diluted in sterile 0.9% (w/v) sodium chloride for administration at
dose levels of 2, 10, and 20 mg/kg yielding final drug concentrations of 0.6 (2
2112
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PHARMACOKINETICS
OF PACLITAXEL
AND CREMOPHOR
EL
mg/kg) and 3 mg/ml (10 and 20 mg/kg). Paclitaxel was also administered at a
dose level of 2 mg/kg with supplemented Cremophor EL-ethanol to mimic the
amount given at the 10-mg/kg dose level with the conventional formulation.
Two "home-made" formulations were prepared as follows: a) 6 mg paclitaxel
were dissolved by sonication in 500 /xl of warm (37°C)Tween 80. Next. 500
tassium phosphate (72:13:15, v/v/v), and UV detection at 280 nm. The lower limit
of quantitation in both plasma and tissues was 0.01% (v/v) of Cremophor EL.
Pharmacokinetic Analysis. All pharmacokinetic parameters were calcu
lated by noncompartmental analysis using the MW/Pharm software package
[MediWare, Groningen, the Netherlands (12)]. The terminal half-life (ttn) was
ju.1ethanol were added. Further dilution was achieved by vigorous stirring and
dropwise addition of 1.00 ml of 0.9% (w/v) sodium chloride, giving a final
drug concentration of 3 mg/ml. Paclitaxel was given at a dose level of 10
mg/kg. b) Solutions of paclitaxel were prepared in dimethylacetamide
by
sonication at concentrations of 1.2 and 6 mg/ml. These solutions were used to
administer paclitaxel at dose levels of 2 and 10 mg/kg, respectively. The
paclitaxel content in these formulations was checked by HPLC. The observed
concentrations were within ±5%of their target values, and no losses occurred
during storage for 24 h at room temperature.
Pharmacokinetic Studies. Drug solutions were administered under light
diethyl ether anesthesia by a single i.v. bolus injection into the tail vein. The
average injection time was 5 s for the Cremophor EL and Tween 80 formu
lations (3.33 ml/kg body weight) and 15 s for the dimethylacetamide-based
calculated by weighted ( 1/Y) linear regression analysis of the data points of the
final log-linear part of the concentration-time curve. The AUC was calculated
formulation ( 1.67 ml/kg body weight). Blood samples were obtained by orbital
bleeding under diethyl ether anesthesia at 5, 15, 30, and 45 min, and 1, 2, 4,
6, 8, 10, 12. 14, 16, 24, and 48 h after administration, using 3-4 animals per
The AUCs of paclitaxel formulated in Cremophor EL-ethanol, given at
dose levels of 2 and 10 mg/kg, follow a bi-exponential decay (Fig. 1). At
the 20-mg/kg dose level, however, a standard compartment-dependent
model was unable to fit the AUC. When the dose of paclitaxel formulated
in Cremophor EL-ethanol was increased from 2 to 10 and 20 mg/kg (i.e.,
5- and 10-fold, respectively), the Cmax increased 30 and 110-fold,
whereas the Cl was simultaneously reduced from 2.37 to 0.33 and 0.15
L/h/kg, respectively (Table 1). When paclitaxel was given at a dose level
of 2 mg/kg with extra Cremophor EL-ethanol to mimic the amount of
vehicle typically given at a dose level of 10 mg/kg, the Cl was 4-fold
lower and the Cmax was 3.3-fold higher relative to 2 mg/kg paclitaxel
time point. Lithium heparin ( 10 /il of 700 USP units/ml per sample) was used
as an anticoagulant. Samples were placed on ice, and plasma was separated
within 5 min by centrifugation at 2100 x g for 10 min at 0°C.At 1, 4, and 8
h after drug administration tissue specimens, including brain, dorsal fat. muscle
(back), breast, organ fat, colon, cecum, small intestine, stomach, liver, gall
bladder (bile), kidneys, lungs, spleen, heart, ovaries, uterus, thymus, and lymph
nodes were collected. Immediately after collection, the samples were placed on
ice and were homogenized with 5-10 volumes of cold (4°C)4% (w/v) aqueous
BSA solution. All samples were stored at —¿
20°Cuntil analysis.
Plasma samples were collected from three cancer patients receiving 175
mg/m2 paclitaxel as a 3-h i.v. infusion. Samples were obtained at 3, 12, and 24
h after start of the infusion and were handled as described previously (2).
Analysis of Paclitaxel. Paclitaxel and its metabolites 3'-p-hydroxypaclitaxel
(I). 6a-hydroxypaclitaxel (II), and 6a,3'-p-dihydroxypaclitaxel
(III) were deter
mined by reversed-phase HPLC with UV detection as described previously (10).
To increase the sensitivity, the assay was performed with a lOOO-fil sample
volume. Accuracy and precision, determined by replicate analysis (n = 4) of
1000-/J.1mouse plasma samples spiked with 10 ng/ml of paclitaxel and metabolites
I-II1, ranged from 90.8 to 111% and £6.1%, respectively, for all four compounds.
Analysis of Cremophor EL. Cremophor EL concentrations in plasma and
tissues were measured by a novel HPLC assay described in detail elsewhere
(11). The method is based on saponification of Cremophor EL in alcoholic
potassium hydroxide USP. followed by chloroform extraction and 1-naphthylamine derivatization of the major fatty acid component of Cremophor EL,
ricinoleic acid, and the internal standard margaric acid. The reaction products
are separated by reversed-phase HPLC using an analytical column packed with
Spherisorb ODS-1 material, a mobile phase of methanol-acetonitrile-10 mM po
by the linear trapezoidal rule and extrapolated to infinity (AUC0.^) by the
equation AUC + Clk. where C represents the mean plasma concentration at the
last sampling point and k the elimination rate constant calculated by k = 0.693/
Ã-1/2.The CmaJ<was put on par with the mean concentration in the plasma
samples collected at 5 min post-drug administration. The Cl was estimated by
the equation Cl = dose/AUC, and the distribution volume (Vd) by Vd = dose/
(AUC-i). The AUCs of Cremophor EL were fitted by a two-compartment open
model using the same program (MW/Pharm).
RESULTS
given without extra Cremophor EL.
With paclitaxel dissolved in dimethylacetamide, the Cl was inde
pendent of the dosage, and the Cmaxvaried proportionally with dosage
within the tested dose range of 2-10 mg/kg. The Cl and Cmaxobserved
with paclitaxel formulated in Tween 80-ethanol corresponded to those
found when the drug was dissolved in dimethylacetamide.
We have compared the levels of paclitaxel and its metabolites in a
variety of tissues of female FVB mice at 1,4, and 8 h after the
administration of 10 mg/kg paclitaxel. Despite the higher plasma
levels after administration in the conventional formulation, the levels
observed in all of the tissues were essentially similar at all time points
with all three formulations. Moreover, no changes occurred in the
tissue distribution of the metabolites (data not shown).
The plasma pharmacokinetic profiles of Cremophor EL after ad
ministration of paclitaxel at dose levels of 2, 10, and 20 mg/kg,
corresponding to 0.17, 0.83, and 1.67 ml/kg of Cremophor EL, re-
.E
"S
Fig. 1. AUCs of pactilaxel of female FVB mice after i.v.
bolus administration of paclitaxel in different formulations at
2 (•),10 (T), and 20 (•)mg/kg in the conventional formu
lation with Cremophor EL-ethanol USP (1:1, v/v); at 2 mg/kg
(V) with supplemented Cremophor EL to mimic the amount
given at the 10-mg/kg dose level in the conventional formu
lation: at 10 mg/kg (D) in Tween 80: and at 2 (O) and 10 (A)
mg/kg in dimethylacetamide. Data points, mean concentra
tion: bars. SEM.
o
O
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PHARMACOKINETICSOF PACLITAXEL AND CREMOPHOR EL
Table 1 Pharmacokinetic
Dose level, paclitaxel
(mg/kg)22lu2021010Formulation"ABBBCCDVolume
parameters
of paclitaxel in mice ai various drug formulations
and dosages
Cremophor EL
(h)1.962.142.162.201.611.501.36vd(L/kg)6.691.741.040.485.
(Hg/ml.h)0.8453.5530.01340.7773.823.76*
(Uh)0.350.320.320.320.430.460.51'1/2
(fig/ml)1.13.4341201.15.15.9AUC
(ml/kg)0.170.830.831.67nonenonenone^max
"A. Cremophor EL-ethanol (1:1, v/v) diluted 1 + 9 in 0.9% (w/v) sodium chloride; B. Cremophor EL-ethanol (1:1, v/v) diluted l + l in 0.9% (w/v) sodium chloride; C,
dimethylacetamide; D, Tween 80-ethanol (1:1, v/v) diluted 1 + 1 in 0.9% (w/v) sodium chloride.
spectively, can be described by a two-compartment open model (Fig.
2). The calculated terminal half-life [fl/2(ß)]was approximately 17 h
and was independent of the dosage (Table 2). The peak plasma level
at the 2-mg/kg paclitaxel dose level was 0.29% (v/v), and increased 7and 16-fold at 5- and 10-fold higher dose levels, respectively (Table
2). The plasma levels of Cremophor EL observed at 24 h after
administration were 0.031 ± 0.003% (v/v), 0.13 ±0.024%, and
0.40 ±0.083% at dose levels of 2, 10, and 20 mg/kg paclitaxel,
respectively. The Cl of Cremophor EL decreased by 23% when the
dose increased from 0.17 to 1.67 mg/kg. In plasma samples collected
from three cancer patients receiving 175 mg/m2 paclitaxel by a 3-h
DISCUSSION
The nonlinear pharmacokinetic behavior of paclitaxel in patients
has now been well established (2-6). Both an overproportional in
crease in Cmax and a reduction in the Cl are found upon dosage
escalation. Although this nonlinearity appears to occur with all ad
ministration schedules, it is more profound when the drug is admin
istered within a short period of time (e.g., 3 h), rather than by a lasting
infusion (24 or 96 h). These findings were thought to be consistent
with saturable processes of elimination and distribution of paclitaxel,
occurring when the plasma concentration of the drug is above a
"saturation point" (4). This assumption inspired these investigators to
intravenous infusion, the plasma levels of Cremophor EL ranged
between 0.66 and 1.22% (v/v) at the end of the infusion and between
0.11 and 0.38% (v/v) at 24 h after the start of the infusion (Table 3).
Cremophor EL levels in mouse tissues were below the lower limit of
detection of the HPLC assay (0.01%, v/v).
develop a mathematical model that could predict the course of the
concentration-time curve for a variety of dosages and infusion times.
The model is very complex and comprises two peripheral and one
metabolite compartments, with Michaelis-Menten dependent elimina
tion. The distribution into peripheral compartment 1 and the formation
of 6a-hydroxypaclitaxel (II) would also be saturable processes (4). In
the present study of paclitaxel disposition in mice, we observed a
similar phenomenon. In line with the results from dosage escalation
studies in patients, the paclitaxel levels in plasma, collected at time
points between 0.5 and 48 h after drug administration, increased more
than proportional, with doses increasing from 2 to 10 mg/kg. The drug
levels observed in most tissues, however, increased only 4- to 7-fold,
which was more or less linear with dose (8). Recent studies have
provided evidence that Cremophor EL can have a major impact on the
pharmacology of paclitaxel, such as modulation of the multidrug
resistance P-glycoprotein pump (13-16). Because relatively large
amounts of Cremophor EL are given concurrently with paclitaxel, we
speculated that this vehicle might influence the plasma pharmacoki-
a
o
0.1%:
0.01%
io
20
30
time (h)
Fig. 2. AUCs of Cremophor EL of female FVB mice after i.v. administration of
paclitaxel formulated in Cremophor EL at 2 (•),10 (O), and 20 mg/kg (•).Dala points,
mean concentration; bars, SEM.
Table 2 Pharmacokinetic
Dose(ml/kg)0.17"
0.836
1.67rCmax
parameters
v/v)0.29
(%,
(mg/ml
h)27.7 •¿
2.14.6AUC
161
361<1/2(l)(h)2.29
netics of paclitaxel. This prompted us to perform a comparative
plasma pharmacokinetic study with paclitaxel given in different for
mulations. The Tween 80-ethanol formulation was chosen because
this vehicle is currently used for docetaxel, a semisynthetic structural
analogue of paclitaxel, which does not appear to exhibit a nonlinear
pharmacokinetic behavior (1). Dimethylacetamide was chosen be
cause it is a relatively nontoxic compound that has been used as a
solvent for a variety of other poorly water-soluble drugs (17). Pacli
taxel formulated in dimethylacetamide was administered in a small
volume and by a slow i.v. injection because a more rapid administration
was associated with local inflammation and necrosis of the tail. No other
toxicities that might be related to the vehicles alone were observed.
The plasma concentration of paclitaxel achieved in humans is in the
of Cremophor EL in mice at three dose levels
2.30
2.49»1/2(8)
(h)17.2
<L/kg)0.158
<L/h/kg)0.00635
17.517.6Va
0.138
0.124Cl
0.00546
0.00488
" Paclitaxel dose. 2 mg/kg.
Paclitaxel dose, 10 mg/kg.
c Paclitaxel dose, 20 mg/kg.
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PHARMACOKINETICS
OF PACLITAXEL
AND CREMOPHOR
EL
Table 3 Cremophor EL plasma levels in female patients with advanced ovarian cancer
treated with a 3-h infusion of 175 mg/m of paclitaxei
Patient
Pactitaxel dose
no.
(mg)123270300330Cremophor
paclitaxei and Cremophor EL levels in mice were in the same order of
magnitude as those found in patients, it is very likely that the effects
v/v)24h0.2850.3780.114
of Cremophor EL also occur in humans.
level3h0.6630.7691.21612
EL
EL do;
(ml)22.525.027.5Cremophor
h0.3270.4040.402(%,
ACKNOWLEDGMENTS
The authors gratefully acknowledge the excellent biotechnical assistance of
Ton Schrauwers.
same range observed in mice receiving 2 and 10 mg/kg paclitaxei in
Cremophor EL-ethanol ( 1). Within this range of dose levels, the nonlin
ear pharmacokinetic behavior of paclitaxei in mice is most profound, with
30- and 40-fold higher Cmax and AUC, respectively. The influence of
Cremophor EL on the pharmacokinetics of paclitaxei was readily shown
from the results obtained in the two groups, which were treated at equal
dose levels (2 mg/kg), but with one group receiving a 5-fold higher
amount of Cremophor EL. Furthermore, with the two other formulations
that do not contain Cremophor EL (Tween 80-ethanol and dimethylacetamide), both distribution and elimination appeared to be linear pro
cesses. These findings demonstrate that within the tested dose range, the
nonlinear pharmacokinetic behavior of paclitaxei in mice is caused by
Cremophor EL exclusively.
Webster et al. ( 18) have developed a bioassay for the determination
of Cremophor EL in human plasma; however, only preliminary results
of Cremophor EL levels in plasma of humans have been presented so
far. We recently developed and validated a very sensitive and accurate
HPLC method for the determination of Cremophor EL in mouse and
human plasma and implemented this assay in the present study.
Cremophor EL levels in mouse plasma follow bi-exponential decay
kinetics. The Vd of Cremophor EL (0.140 L/kg) is less than the
volume of the plasma and the extracellular compartment (approxi
mately 0.2 L/kg), indicating that the tissue distribution of Cremophor
EL is insignificant. This is in line with our observation that Cremo
phor EL levels in tissues are undetectable. The terminal half-life of
Cremophor EL is relatively long, resulting in a sustained presence of
substantial levels at 24 h after paclitaxei administration. The discrep
ancies between our results (Table 3) and those of Webster et al. [who
reported Cremophor EL levels of 0.09-0.20% (v/v) at the end of a 3-h
i.v. infusion of 135 or 175 mg/m2 paclitaxei; Ref. 18] might be due to
the relative inaccuracy of the bioassay, permitting only an estimation
of the plasma concentration of this triglycéride.Because the plasma
concentrations of Cremophor EL in mice and humans are within the
same range, it is very likely that Cremophor EL plays a pivotal role in
the nonlinear pharmacokinetic behavior of paclitaxei in humans.
The mechanism of the dosage-dependent interaction of Cremophor
EL with the pharmacokinetics of paclitaxei is not clear. It has been
reported that under in vitro conditions, Cremophor EL is capable of
reversing P-glycoprotein-mediated
multidrug resistance (13-16).
However, although modulation of P-glycoprotein by Cremophor EL
might certainly result in a diminished Cl (19), it does not explain the
apparent saturable tissue distribution. Furthermore, the undetectable
Cremophor EL levels in tissues suggest that this compound may not
be a very effective multidrug resistance modulator in vivo at all.
Another possibility might be the influence of Cremophor EL on
serum lipoproteins, as reported previously (20, 21). They demon
strated that Cremophor EL induced the appearance of a lipoprotein
dissociation product for which paclitaxei has a high affinity. Alterna
tively, Cremophor EL, like many other amphipatic molecules, forms
micelles in aqueous solutions (22). It is possible that such micelles act
as a high-affinity drug-transporting sanctuary, causing an apparently
reduced non-protein bound free drug fraction.
In conclusion, this study with mice provides evidence that the
pharmaceutical vehicle Cremophor EL is a principal determinant in
the nonlinear pharmacokinetic behavior of paclitaxei (Taxol). As the
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Nonlinear Pharmacokinetics of Paclitaxel in Mice Results from
the Pharmaceutical Vehicle Cremophor EL
Alex Sparreboom, Olaf van Tellingen, Willem J. Nooijen, et al.
Cancer Res 1996;56:2112-2115.
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