nonlinear pharmacokinetics of paclitaxel in mice results ... · level, a mouse of 24 g receives...

[CANCER RESEARCH 56. 2112-2115, May 1. 1996]

Nonlinear Pharmacokinetics of Paclitaxel in Mice Results from the Pharmaceutical

Vehicle Cremophor ELAlex Sparreboom,1 Olaf van Tellingen, Willem J. Nooijen, and Jos H. Beijnen

Department of Clinical Chemistry; Antimi van Leeuwenhoek HuÃs,the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam Â¡A.S., O. v. T., W. J. N.l. Department>ifPharmacy. Slotenaart Hospital, Louwesweg 6, 1066 EC. Amsterdam Â¡J.H. B.Â¡and Department of Analysis and Toxicology. Faculty of Pharmacy: Utrecht University: P.O. Box80082. 3508 TB Utrecht Â¡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, thedrug is formulated in a mixture of Cremophor EL and ethanol (1:1, v/v;Taxol). We hypothesized that the substantial amounts of concurrentlyadministered Cremophor EL could have a major influence on the phar-

macokinetic behavior of paclitaxel. To determine the effect of the pharmaceutical vehicle Cremophor EL on the disposition of paclitaxel, femaleFVB mice received paclitaxel by i.v. injection at dose levels of 2, 10, and20 mg/kg by appropriate (standard) dilution of the commercially availableformulation of paclitaxel (Taxol) with saline. The drug was also given at2 mg/kg with supplemented Cremophor EL-ethanol to achieve the same

amount of vehicle as by standard administration of 10 mg/kg. Furthermore, paclitaxel formulations in Tween 80-ethanol (1:1, v/v) and dimeth-

ylacetamide were tested. Plasma samples were collected between 5 minand 48 h, and tissue specimens were sampled at 1, 4, and 8 h after drugadministration. Paclitaxel and metabolites were quantified by high-per

formance liquid chromatography. Cremophor EL levels were determinedby a novel high-performance liquid chromatography procedure. For com

parative reasons, Cremophor EL was also assayed in plasma samples fromthree patients receiving a 3-h i.v. infusion of 175 mg/m2 of paclitaxel. A

marked nonlinear pharmacokinetic behavior of paclitaxel was observedwhen 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 and20 mg/kg, respectively. When 2 mg/kg were given with an amount ofCremophor EL-ethanol matching that of the 10-mg/kg dose level, theclearance was 0.56 L/h/kg. If administered at 10 mg/kg in Tween 80-

ethanol or at 2 and 10 mg/kg in dimethylacetamide, the clearances were2.66, 2.57, and 2.62 L/h/kg, respectively. Despite the fact that much higherplasma levels of paclitaxel are reached when given in the CremophorEL-ethanol formulation, the tissue levels were essentially similar with all

tested drug preparations. The Cremophor EL levels in patients were in thesame order of magnitude as those observed in mice after administration of2 and 10 mg/kg. These data demonstrate that Cremophor EL has aprofound effect on the pharmacokinetics of paclitaxel in mice. BecauseCremophor EL levels in mice and humans are within the same range, it isvery likely that Cremophor EL also contributes substantially to the nonlinear 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 antitumordrugs, which act by stabilizing microtubules (1). It has already become an important drug in the management of ovarian, breast, andlung cancers (1). A substantial number of clinical pharmacokineticstudies with paclitaxel have been performed to date and have showna nonlinear pharmacokinetic behavior (2-6). A more than proportional 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 with18 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.

â€¢¿�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 tissuedistribution are saturable processes (2-4). Complex mathematical

models have been developed, which appear to give a reasonable fit ofthe paclitaxel AUCs (3, 4). However, the fundamental reasons for thisnonlinear pharmacokinetic behavior are still poorly understood. Previous studies on drug disposition in mice have suggested that nonlinear pharmacokinetics also occurs in this species (7, 8).

Because of its poor water solubility, paclitaxel is currently formulated in a mixture of polyoxyethyleneglycerol triricinoleate 35 (Cremophor EL) and dehydrated ethanol USP (1:1, v/v). Before administration, 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 1.2mg/ml (1). Considerable amounts of Cremophor EL are given concurrently with paclitaxel. In fact, the maximum dose of paclitaxel thatcan be administered to mice by i.v. bolus injection (i.e., 20 mg/kg) isdictated by the acute lethal toxicity of this vehicle (7). At this doselevel, a mouse of 24 g receives about 40 /xl of pure Cremophor EL.Although humans receive relatively less Cremophor EL with paclitaxeltherapy (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 ofpaclitaxel cannot be ruled out because there are no comparative dataavailable on the pharmacokinetics of this substance in mice and humans.

In the present study, we have investigated the pharmacokinetics ofpaclitaxel at different dosages and drug formulations to determine theeffects of Cremophor EL on the disposition of paclitaxel. We alsopresent a comprehensive analysis of the pharmacokinetics of Cremophor EL in mice and preliminary results in humans by using a novelanalytical method based on HPLC.

MATERIALS AND METHODS

Chemicals. Paclitaxel (solid; batch 80617492D), commercially availablepaclitaxel 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 paclitaxel and 2'-methylpaclitaxel was higher than 98.0%. Reference standards ofthe 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 originatedfrom Organon Teknika BV (Boxtel, the Netherlands). Cremophor EL [specificgravity (25Â°C/25Â°C)= 1.05-1.06; lot 32H0925] and margaric acid were

purchased from Sigma Chemical Co. (St. Louis, MO). All other chemicalswere 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 Netherlands). 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 housedaccording to institutional guidelines in a protected environment in conventional plastic cages and maintained on an automatic 12-h lighting cycle at atemperature of 22-24Â°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 atdose levels of 2, 10, and 20 mg/kg yielding final drug concentrations of 0.6 (2

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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 adose level of 2 mg/kg with supplemented Cremophor EL-ethanol to mimic theamount 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 (37Â°C)Tween 80. Next. 500

ju.1ethanol were added. Further dilution was achieved by vigorous stirring anddropwise addition of 1.00 ml of 0.9% (w/v) sodium chloride, giving a finaldrug concentration of 3 mg/ml. Paclitaxel was given at a dose level of 10mg/kg. b) Solutions of paclitaxel were prepared in dimethylacetamide bysonication at concentrations of 1.2 and 6 mg/ml. These solutions were used toadminister paclitaxel at dose levels of 2 and 10 mg/kg, respectively. Thepaclitaxel content in these formulations was checked by HPLC. The observedconcentrations were within Â±5%of their target values, and no losses occurredduring storage for 24 h at room temperature.

Pharmacokinetic Studies. Drug solutions were administered under lightdiethyl ether anesthesia by a single i.v. bolus injection into the tail vein. Theaverage injection time was 5 s for the Cremophor EL and Tween 80 formulations (3.33 ml/kg body weight) and 15 s for the dimethylacetamide-based

formulation ( 1.67 ml/kg body weight). Blood samples were obtained by orbitalbleeding 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

time point. Lithium heparin ( 10 /il of 700 USP units/ml per sample) was usedas an anticoagulant. Samples were placed on ice, and plasma was separatedwithin 5 min by centrifugation at 2100 x g for 10 min at 0Â°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, gallbladder (bile), kidneys, lungs, spleen, heart, ovaries, uterus, thymus, and lymphnodes were collected. Immediately after collection, the samples were placed onice and were homogenized with 5-10 volumes of cold (4Â°C)4% (w/v) aqueousBSA solution. All samples were stored at â€”¿�20Â°Cuntil analysis.

Plasma samples were collected from three cancer patients receiving 175mg/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 samplevolume. Accuracy and precision, determined by replicate analysis (n = 4) of1000-/J.1mouse plasma samples spiked with 10 ng/ml of paclitaxel and metabolitesI-II1, ranged from 90.8 to 111% and Â£6.1%, respectively, for all four compounds.

Analysis of Cremophor EL. Cremophor EL concentrations in plasma andtissues were measured by a novel HPLC assay described in detail elsewhere(11). The method is based on saponification of Cremophor EL in alcoholicpotassium hydroxide USP. followed by chloroform extraction and 1-naphthyl-

amine derivatization of the major fatty acid component of Cremophor EL,ricinoleic acid, and the internal standard margaric acid. The reaction productsare separated by reversed-phase HPLC using an analytical column packed withSpherisorb ODS-1 material, a mobile phase of methanol-acetonitrile-10 mM po

tassium phosphate (72:13:15, v/v/v), and UV detection at 280 nm. The lower limitof quantitation in both plasma and tissues was 0.01% (v/v) of Cremophor EL.

Pharmacokinetic Analysis. All pharmacokinetic parameters were calculated by noncompartmental analysis using the MW/Pharm software package[MediWare, Groningen, the Netherlands (12)]. The terminal half-life (ttn) was

calculated by weighted ( 1/Y) linear regression analysis of the data points of thefinal log-linear part of the concentration-time curve. The AUC was calculated

by the linear trapezoidal rule and extrapolated to infinity (AUC0.^) by theequation AUC + Clk. where C represents the mean plasma concentration at thelast sampling point and k the elimination rate constant calculated by k = 0.693/

Ã1/2.The CmaJ<was put on par with the mean concentration in the plasmasamples collected at 5 min post-drug administration. The Cl was estimated bythe 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

The AUCs of paclitaxel formulated in Cremophor EL-ethanol, given atdose levels of 2 and 10 mg/kg, follow a bi-exponential decay (Fig. 1). Atthe 20-mg/kg dose level, however, a standard compartment-dependent

model was unable to fit the AUC. When the dose of paclitaxel formulatedin 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 0.15L/h/kg, respectively (Table 1). When paclitaxel was given at a dose levelof 2 mg/kg with extra Cremophor EL-ethanol to mimic the amount ofvehicle typically given at a dose level of 10 mg/kg, the Cl was 4-foldlower and the Cmax was 3.3-fold higher relative to 2 mg/kg paclitaxel

given without extra Cremophor EL.With paclitaxel dissolved in dimethylacetamide, the Cl was inde

pendent of the dosage, and the Cmaxvaried proportionally with dosagewithin the tested dose range of 2-10 mg/kg. The Cl and Cmaxobservedwith 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 theadministration of 10 mg/kg paclitaxel. Despite the higher plasmalevels after administration in the conventional formulation, the levelsobserved in all of the tissues were essentially similar at all time pointswith all three formulations. Moreover, no changes occurred in thetissue distribution of the metabolites (data not shown).

The plasma pharmacokinetic profiles of Cremophor EL after administration 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-

Fig. 1. AUCs of pactilaxel of female FVB mice after i.v.bolus administration of paclitaxel in different formulations at2 (â€¢),10 (T), and 20 (â€¢)mg/kg in the conventional formulation with Cremophor EL-ethanol USP (1:1, v/v); at 2 mg/kg

(V) with supplemented Cremophor EL to mimic the amountgiven 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 concentration: bars. SEM.

.E"S

oO

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PHARMACOKINETICSOF PACLITAXEL AND CREMOPHOR EL

Table 1 Pharmacokinetic parameters of paclitaxel in mice ai various drug formulations and dosages

Dose level, paclitaxel(mg/kg)22lu2021010Formulation"ABBBCCDVolume

Cremophor EL(ml/kg)0.170.830.831.67nonenonenone^max(fig/ml)1.13.4341201.15.15.9AUC(Hg/ml.h)0.8453.5530.01340.7773.823.76*(Uh)0.350.320.320.320.430.460.51'1/2(h)1.962.142.162.201.611.501.36vd(L/kg)6.691.741.040.485.975.675.22CI(L/h/kg)2.370.560.330.152.572.622.66

"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 [f l/2(ÃŸ)]was approximately 17 h

and was independent of the dosage (Table 2). The peak plasma levelat the 2-mg/kg paclitaxel dose level was 0.29% (v/v), and increased 7-and 16-fold at 5- and 10-fold higher dose levels, respectively (Table

2). The plasma levels of Cremophor EL observed at 24 h afteradministration were 0.031 Â±0.003% (v/v), 0.13 Â±0.024%, and0.40 Â±0.083% at dose levels of 2, 10, and 20 mg/kg paclitaxel,respectively. The Cl of Cremophor EL decreased by 23% when thedose increased from 0.17 to 1.67 mg/kg. In plasma samples collectedfrom three cancer patients receiving 175 mg/m2 paclitaxel by a 3-h

intravenous infusion, the plasma levels of Cremophor EL rangedbetween 0.66 and 1.22% (v/v) at the end of the infusion and between0.11 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 ofdetection of the HPLC assay (0.01%, v/v).

ao

0.1%:

0.01%io 20 30

time (h)

Fig. 2. AUCs of Cremophor EL of female FVB mice after i.v. administration ofpaclitaxel formulated in Cremophor EL at 2 (â€¢),10 (O), and 20 mg/kg (â€¢).Dala points,mean concentration; bars, SEM.

DISCUSSION

The nonlinear pharmacokinetic behavior of paclitaxel in patientshas now been well established (2-6). Both an overproportional in

crease in Cmax and a reduction in the Cl are found upon dosageescalation. Although this nonlinearity appears to occur with all administration schedules, it is more profound when the drug is administered within a short period of time (e.g., 3 h), rather than by a lastinginfusion (24 or 96 h). These findings were thought to be consistentwith 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

develop a mathematical model that could predict the course of theconcentration-time curve for a variety of dosages and infusion times.

The model is very complex and comprises two peripheral and onemetabolite compartments, with Michaelis-Menten dependent elimina

tion. The distribution into peripheral compartment 1 and the formationof 6a-hydroxypaclitaxel (II) would also be saturable processes (4). In

the present study of paclitaxel disposition in mice, we observed asimilar phenomenon. In line with the results from dosage escalationstudies in patients, the paclitaxel levels in plasma, collected at timepoints between 0.5 and 48 h after drug administration, increased morethan proportional, with doses increasing from 2 to 10 mg/kg. The druglevels observed in most tissues, however, increased only 4- to 7-fold,

which was more or less linear with dose (8). Recent studies haveprovided evidence that Cremophor EL can have a major impact on thepharmacology of paclitaxel, such as modulation of the multidrugresistance P-glycoprotein pump (13-16). Because relatively large

amounts of Cremophor EL are given concurrently with paclitaxel, wespeculated that this vehicle might influence the plasma pharmacoki-

netics of paclitaxel. This prompted us to perform a comparativeplasma pharmacokinetic study with paclitaxel given in different formulations. The Tween 80-ethanol formulation was chosen because

this vehicle is currently used for docetaxel, a semisynthetic structuralanalogue of paclitaxel, which does not appear to exhibit a nonlinearpharmacokinetic behavior (1). Dimethylacetamide was chosen because it is a relatively nontoxic compound that has been used as asolvent for a variety of other poorly water-soluble drugs (17). Pacli

taxel formulated in dimethylacetamide was administered in a smallvolume and by a slow i.v. injection because a more rapid administrationwas associated with local inflammation and necrosis of the tail. No othertoxicities that might be related to the vehicles alone were observed.

The plasma concentration of paclitaxel achieved in humans is in the

Table 2 Pharmacokinetic parameters of Cremophor EL in mice at three dose levels

Dose(ml/kg)0.17"

0.8361.67rCmax

(%,v/v)0.29

2.14.6AUC

(mg/ml â€¢¿�h)27.7

161361<1/2(l)(h)2.29

2.302.49Â»1/2(8)

(h)17.2

17.517.6Va

<L/kg)0.158

0.1380.124Cl

<L/h/kg)0.00635

0.005460.00488

" 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 cancertreated with a 3-h infusion of 175 mg/m of paclitaxei

Patient Pactitaxel doseno.(mg)123270300330Cremophor

EL do;(ml)22.525.027.5Cremophor

ELlevel3h0.6630.7691.21612

h0.3270.4040.402(%,

v/v)24h0.2850.3780.114

same range observed in mice receiving 2 and 10 mg/kg paclitaxei inCremophor EL-ethanol ( 1). Within this range of dose levels, the nonlin

ear pharmacokinetic behavior of paclitaxei in mice is most profound, with30- and 40-fold higher Cmax and AUC, respectively. The influence of

Cremophor EL on the pharmacokinetics of paclitaxei was readily shownfrom the results obtained in the two groups, which were treated at equaldose levels (2 mg/kg), but with one group receiving a 5-fold higher

amount of Cremophor EL. Furthermore, with the two other formulationsthat do not contain Cremophor EL (Tween 80-ethanol and dimethylac-

etamide), both distribution and elimination appeared to be linear processes. These findings demonstrate that within the tested dose range, thenonlinear pharmacokinetic behavior of paclitaxei in mice is caused byCremophor EL exclusively.

Webster et al. ( 18) have developed a bioassay for the determinationof Cremophor EL in human plasma; however, only preliminary resultsof Cremophor EL levels in plasma of humans have been presented sofar. We recently developed and validated a very sensitive and accurateHPLC method for the determination of Cremophor EL in mouse andhuman 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 thevolume of the plasma and the extracellular compartment (approximately 0.2 L/kg), indicating that the tissue distribution of CremophorEL is insignificant. This is in line with our observation that Cremophor EL levels in tissues are undetectable. The terminal half-life of

Cremophor EL is relatively long, resulting in a sustained presence ofsubstantial levels at 24 h after paclitaxei administration. The discrepancies between our results (Table 3) and those of Webster et al. [whoreported Cremophor EL levels of 0.09-0.20% (v/v) at the end of a 3-hi.v. infusion of 135 or 175 mg/m2 paclitaxei; Ref. 18] might be due to

the relative inaccuracy of the bioassay, permitting only an estimationof the plasma concentration of this triglycÃ©ride.Because the plasmaconcentrations of Cremophor EL in mice and humans are within thesame range, it is very likely that Cremophor EL plays a pivotal role inthe 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 beenreported that under in vitro conditions, Cremophor EL is capable ofreversing 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 theapparent saturable tissue distribution. Furthermore, the undetectableCremophor EL levels in tissues suggest that this compound may notbe a very effective multidrug resistance modulator in vivo at all.

Another possibility might be the influence of Cremophor EL onserum lipoproteins, as reported previously (20, 21). They demonstrated that Cremophor EL induced the appearance of a lipoproteindissociation product for which paclitaxei has a high affinity. Alternatively, Cremophor EL, like many other amphipatic molecules, formsmicelles in aqueous solutions (22). It is possible that such micelles actas a high-affinity drug-transporting sanctuary, causing an apparentlyreduced non-protein bound free drug fraction.

In conclusion, this study with mice provides evidence that thepharmaceutical vehicle Cremophor EL is a principal determinant inthe nonlinear pharmacokinetic behavior of paclitaxei (Taxol). As the

paclitaxei and Cremophor EL levels in mice were in the same order ofmagnitude as those found in patients, it is very likely that the effectsof Cremophor EL also occur in humans.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the excellent biotechnical assistance ofTon Schrauwers.

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1996;56:2112-2115. Cancer Res Alex Sparreboom, Olaf van Tellingen, Willem J. Nooijen, et al. the Pharmaceutical Vehicle Cremophor ELNonlinear Pharmacokinetics of Paclitaxel in Mice Results from

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