Disposition kinetics of taxanes in peritoneal dissemination.

Abstract

Treatment of cancers in the abdominal cavity, such as peritoneal dissemination, is difficult, but in principle intraperitoneal administration of anticancer drugs is expected to be preferable to systemic administration. Taxane anticancer drugs are used to treat gastric cancer patients with peritoneal dissemination. They are administered as micellar preparations, Taxol and Taxotere, which consist of paclitaxel in Cremophor EL (crEL) and docetaxel in Polysorbate-80 (PS-80), respectively. In this paper we review the disposition kinetics of taxane anticancer drugs after intraperitoneal administration in peritoneal dissemination patients and animal models and also discuss the effect of the surfactant vehicle on the behavior of taxanes.

Full text

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Hindawi Publishing Corporation
Gastroenterology Research and Practice
Volume 2012, Article ID 963403, 9 pages
doi:10.1155/2012/963403
Review Article
DispositionKineticsof Taxanes inPeritonealDissemination
Ken’ichi Miyamoto,Tsutomu Shimada,KazukiSawamoto, Yoshimichi Sai,
andYutaka Yonemura
Department of Pharmacy, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa 920-8641, Japan
Correspondence should be addressed to Ken’ichi Miyamoto, miyaken@staff.kanazawa-u.ac.jp
Received 6 January 2012; Accepted 14 February 2012
Academic Editor: Yan Li
Copyright © 2012 Ken’ichi Miyamoto et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Treatment of cancers in the abdominal cavity, such as peritoneal dissemination, is difficult, but in principle intraperitoneal
administration of anticancer drugs is expected to be preferable to systemic administration. Taxane anticancer drugs are used
to treat gastric cancer patients with peritoneal dissemination. They are administered as micellar preparations, Taxol and Taxotere,
which consist of paclitaxel in Cremophor EL (crEL) and docetaxel in Polysorbate-80 (PS-80), respectively. In this paper we review
the disposition kinetics of taxane anticancer drugs after intraperitoneal administration in peritoneal dissemination patients and
animal models and also discuss the effect of the surfactant vehicle on the behavior of taxanes.
1.Introduction
Taxane alkaloids, paclitaxel and docetaxel, are widely used
in the treatment of various cancers. Their anticancer activity
is related to stabilization of microtubule assembly, and they
cause mitotic arrest in the G2M phase of the cell cycle [1].
Paclitaxel and docetaxel have similar chemical and physical
characteristics, as shown in Figure 1, and are barely soluble
in various solvents. They are therefore used as micellar
preparations, Taxol and Taxotere, which consist of paclitaxel
in Cremophor EL (crEL) and docetaxel in Polysorbate-80
(PS-80), respectively (Figure 2).
Chemotherapy for patients with peritoneal dissemina-
tion has generally been unsatisfactory. Peritoneal cancer
occurs in about 10–15% of patients with gastric cancer
and in about 50–60% of relapsed cases after gastrectomy.
In general, however, treatment of the peritoneal cancer is
ineffective, and the 5-year survival rate is extremely low even
after multidisciplinary treatment, such as surgical resection,
radiotherapy, and chemotherapy. In most cases, anticancer
drugs have been given by systemic administration. But,
the peritoneal cavity acts as a sanctuary against systemic
chemotherapy because of the existence of a blood-peritoneal
barrier consisting of stromal tissue between mesothelial cells
and submesothelial blood capillaries [2]. Thus, inadequate
therapeutic effects might be due at least in part to failure of
the drugs to reach abdominal cancerous tissues at sufficient
concentration to eradicate the cancer. The intraperitoneal
(i.p.) dosage route might be better than systemic administra-
tion for treatment of peritoneal dissemination, and it would
be expected to produce a higher drug concentration in the
abdominal cavity and to exhibit a lower systemic toxicity
compared with intravenous (i.v.) administration. Fushida et
al. [3, 4] and Yonemura et al. [5] tried the i.p. infusion
of taxane anticancer drugs in gastric cancer patients with
peritoneal dissemination and reported that the treatment
was more effective, with fewer side effects, than systemic
i.v. administration. Sugarbaker et al. [6] have reviewed
perioperative intraperitoneal chemotherapy; they noted that
the ratio of the area under the drug concentration-time
curve (AUC) in the peritoneal cavity and AUC in plasma
(AUCa/AUCp) was much larger for paclitaxel and docetaxel
than for other anticancer drugs, suggesting that taxanes may
be effective when used in early postoperative intraperitoneal
chemotherapy, without severe systemic toxicity. Moreover,
i.p. docetaxel appeared to be more effective than pacli-
taxel on peritoneal dissemination. Here, we review the
disposition kinetics of taxanes after i.p. administration of
taxane preparations and discuss the relationship between
the pharmacokinetic characteristics and anticancer effects of

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2 Gastroenterology Research and Practice
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H
HO
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O
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Docetaxel
hydrate
O
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OH
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OC
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H2O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H3C
H3C
H3C
H3C
Taxotere®injection contains
Taxotere®
29.5% .
Mw: 861.94
Octanol/water: logP = 3.2
Octanol/water: logP = 3.7
Taxol®
Paclitaxel
Cremophor el 50%
Taxol®injection contains
Mw: 853.92
Polysorbate-80
Figure 1: Chemical structures of taxane anticancer drugs. Circles indicate the differences between docetaxel and paclitaxel.
taxanes, as well as the influence of the micellar surfactant
vehicles.
2.DispositionKinetics inPatients with
PeritonealCancers
We investigated changes of taxane concentration in the
abdominal cavity and peripheral blood after i.p. admin-
istration in advanced gastric cancer patients with peri-
tonealdissemination [7].Taxol(120mg,180mg) or Taxotere
(60mg,80mg) was dissolved in 1L of physiological saline
(final concentration of surfactant; crEL: 1.1–1.6% for Taxol,
PS-80: 0.15–0.2% for Taxotere). and the preparation was
infused into the peritoneal cavity of nine patients for 1h.
Blood and ascites samples were collected at designated time
intervals, and the concentrations of paclitaxel and docetaxel
weremeasuredusingamodificationofthehigh-performance
liquid chromatography method of Vergniol et al. [8] and
Loos et al. [9].
When Taxol (120 and 180mg) was intraperitoneally in-
fused at a volume of 1L for 1h, the maximum peritoneal
concentrationsofpaclitaxeljustaftertheinfusionwereabout
110 and 190μg/mL, respectively, and decreased to 16 and
19μg/mL, respectively, after 24h. The plasma concentration
reached maximum levels of 38 and 54ng/mL, respectively,
within 3h after the infusion and fell below the detection
limit (5ng/mL) after 24h. On the other hand, after 1h
infusion of Taxotere (60 and 80mg/L), the maximum peri-
toneal concentrations of docetaxel were 29 and 40μg/mL,
respectively. These concentrations were about a half of the
calculated initial concentration of docetaxel, suggesting that
thedrugwasdistributedtotheperitonealtissuesorelsewhere
during infusion. The peritoneal concentration was about 1
to 6μg/mL after 24h. The plasma concentration reached the
maximum levels of about 112 and 144ng/mL, respectively,
within 2h after the infusion, then decreased to 5 to 10% of
the maximum after 24h.
Calculation of the pharmacokinetic parameters in ascitic
fluid indicated that the distribution volume (Vda) and the
clearance (CLa) of docetaxel were two to three times than
those of paclitaxel. Among the pharmacokinetic parameters
in plasma of these drugs, Vdp, and CLp of paclitaxel were
larger than those of docetaxel, but the AUCp, 0−25 of
docetaxeltendedtobelargerthanthatofpaclitaxel.Theratio
of AUC in ascitic fluid and AUC in plasma (AUCa/AUCp)
was 500 to 1700 for paclitaxel and 50 to 100 for docetaxel
(Table 1).Similarly,ithasbeenreportedthattheAUCa/AUCp
of paclitaxel (about 1,000) [10, 11] was larger than that
of docetaxel (about 200) [12, 13] after i.p. infusion. These
results suggest that after infusion of taxane preparations into
the peritoneal cavity, docetaxel is more easily transferred to
peripheral blood vessels than paclitaxel. Namely, after i.p.
infusion of Taxol the peritoneal concentration of paclitaxel

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Gastroenterology Research and Practice3
(CH2.CH2−O)x
(CH2.CH2−O)y
(CH2)7-CH = CH–CH2-CHOH–(CH2)5-CH3
(CH2)7-CH = CH–CH2-CHOH–(CH2)5-CH3
CH2-O—
–CO–O—
(CH2.CH2−O)z
(CH2)7-CH = CH–CH2-CHOH–(CH2)5-CH3
CH2-O—
–CO–O—
CH-O—
–CO–O—
Cremophor EL®(CrEL)
(x + y +z ∼35)
Polysorbate-80®(PS-80)
H—((CH2)2
O)w–O
—
O—((CH2)2
O)y–H
—
O—((CH2
O)x–H
—
O—((CH2)2
O)z–CO—(CH2)7–HC = CH—(CH2)6 CH3
—–
(w +x + y +z ∼ 80)
Figure 2: Chemical structures of the major components of Cremophor EL and Polysorbate-80.
Table 1: The values of AUC of paclitaxel and docetaxel in plasma and ascitic fluid after an i.p. infusion of Taxol and Taxotere in patients with
peritoneal tumor [7].
AUCp
(mg∗hr/L)
2.57 ± 1.43
1.30 ± 0.86
6.65 ± 3.75
2.27 ± 0.65
AUCa
(mg∗hr/L)
1,298 ± 238
2,214 ± 128
370 ± 87
238 ± 24
Ratio of
AUCa/AUCp
Paclitaxel
120mg
505
180mg1705
Docetaxel
60mg
56
80mg
105
The value of AUC was calculated from 0 to 25h including the period of the infusion administration.
Each value represents the mean ± SE of three patients.
∗Significantly different from Taxotere at P < 0.01.
was well maintained for a long time and permeation into
the systemic circulation was low, suggesting that paclitaxel
should be effective against peritoneal cancers, and side
effects, such as bone marrow depression, should be weak.
In the case of intraperitoneally administered Taxotere, the
concentrations of docetaxel in the peritoneal cavity and
peripheral plasma were above the cytotoxic concentration
(in vitro IC50: 4–35ng/mL) [14], so this anticancer drug may
exhibit anticancer action against peritoneal cancers but may
also cause systemic side effects.
3.DispositionKinetics inPeritoneal
DisseminationTumor Model Animals
The rat ascites hepatoma cell line AH130 was established
as transplantable tumor by Yoshida [16]. This cell line is
maintained by i.p. passage at weekly intervals in female
Donryu rats and is widely used to prepare animal models
of peritoneal cancer dissemination. The pharmacokinetic
behavior of taxane anticancer drugs and the effects of
their micellar formulation vehicles have been studied using

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4Gastroenterology Research and Practice
Table 2: The values of AUC of paclitaxel and docetaxel in plasma and ascitic fluid after an i.p. injection of Taxol and Taxotere into AH130
tumor-bearing rats [15].
kaAUCp
(mg∗hr/L)
17.6 ± 5.8∗
8.50 ± 3.27
AUCa
(mg∗hr/L)
7,480 ± 255∗
1,300 ± 191
Ratio of
AUCa/AUCp
425
153
(hr−1)
Paclitaxel
Docetaxel
0.0424 ± 0.0011∗
0.325 ± 0.043
The value of AUC was calculated from 0 to 24 h after an i.p. administration of 40 mg/kg of each drug.
ka: the apparent first-order absorption rate constant from the peritoneal cavity.
Each value represents the mean ± SD of three rats.
∗Significantly different from Taxotere at P < 0.01.
0
4812 24
Time (hr)
0.01
0.1
1
10
100
1000
Concentration (µg/mL)
Figure 3: Time courses of paclitaxel (circles) or docetaxel (trian-
gles) concentration in ascitic fluid (closed symbols) and plasma
(open symbols) after an i.p. injection of 40mg/kg of Taxol or
Taxotere into AH130 tumor-bearing rats [15]. Each point with bar
represents the mean ± SD of three rats.
this model [15]. Four-week-old female Donryu rats were
inoculated with 2 × 106AH130 cells into the peritoneal
cavity and used for experiments after 1 to 2 weeks, following
anovernightfast.TaxolorTaxoterewasgivenbyi.p.injection
at a dose of 40mg/kg in a 20mL volume containing 0.2%
blue dextran as a volume marker; the resulting peritoneal
solutions contained 4.2%crEL for paclitacel and 1.5%PS-
80 for docetaxel, which are close to the concentrations used
in the case of i.v. injection of taxanes in the clinic. In the
case of i.v. injection, 5mg/kg of each drug in a volume of
200μL was administered by bolus injection into the tail vein.
After i.p. or i.v. administration of taxanes to the AH130-
bearing rats, the concentrations of drugs in ascitic fluid,
free cancer cells, and plasma obtained from the jugular vein
were measured at designated time intervals. Solid cancers
in the peritoneal cavity were excised after the rats had been
killedbydecapitation,andthedrugswereextractedandtheir
concentrations were measured.
After i.p. administration of taxanes, the ascitic concen-
tration of paclitaxel decayed very slowly, whereas that of doc-
etaxel decreased rapidly. The plasma concentrations of both
drugs were very low, but that of paclitaxel increased until
4h and then remained at a plateau, while that of docetaxel
0
2
4
6
8
10
12
02612
24
Time (hr)
Concentration (µg/4×106cells)
Figure 4: Time courses of paclitaxel (circles) or docetaxel (tri-
angles) concentration in free tumor cells in the peritoneal cavity
after an i.p. injection of 40mg/kg of Taxol or Taxotere into AH130
tumor-bearing rats [15]. Each point with bar represents the mean
± SD of three rats.
reachedthemaximumat1.5handthendecreased(Figure 3).
The values of AUCp, 0–24h, and AUCa, 0–24h of paclitaxel
were significantly larger, by about 2- and 6-fold, respectively,
than those of docetaxel, and the apparent first-order absorp-
tionrateconstantfromtheperitonealcavity(ka)ofpaclitaxel
was extremely small (Table 2). The AUCa/AUCp ratio of
paclitaxel was much larger than that of docetaxel. These
results indicate that paclitaxel was retained at much higher
concentration than docetaxel in the peritoneal cavity after
i.p.administrationoftaxanepreparations,andthetransferof
paclitaxel into the systemic circulation was much lower than
that of docetaxel, in agreement with clinical findings [7, 10–
13]. Figure 4 shows the changes of taxane concentration in
free cancer cells in the peritoneal cavity after i.p. adminis-
tration of Taxol and Taxotere (each 40mg/kg). The concen-
tration of paclitaxel was very low after Taxol administration,
while that of docetaxel was high just after Taxotere admin-
istration and then decreased gradually in parallel with the
decay of the peritoneal concentration. On the other hand, at
1hafteri.p.administration,theconcentrationofpaclitaxelin
solid cancer tissue growing in the peritoneum (1.3 ± 0.2μg/g
tissue) was lower than that of docetaxel (4.1 ± 2.8μg/g
tissue). Figure 5 shows the apparent concentration ratio in
solidcancertissueversusplasma(Kp,app)1hafteri.p.ori.v.
administration. No marked difference was observed between

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Gastroenterology Research and Practice5

0
2
4
6
8
10
12
14
κ
Paclitaxel
∗
Docetaxel
Figure 5: Values of apparent solid tumor to plasma concen-
tration ratio (Kp, app) of paclitaxel and docetaxel 1h after an
i.p. (40mg/kg, open column) or i.v. (5mg/kg, closed column)
injection of Taxol and Taxotere into AH130 tumor-bearing rats
[15]. Each column with bar represents the mean ± SD of three rats.
∗Significantly different from docetaxel at P < 0.05.
the Kp,app values of these drugs after i.p. administration,
but after i.v. administration the Kp, app of paclitaxel was
significantly smaller than that of docetaxel. These results
indicate that after i.p. administration of Taxol, paclitaxel was
retained at high concentration in the peritoneal cavity and
was not readily transferred into either the systemic circula-
tion or cancer cells and tissues. The distribution of paclitaxel
into cancer tissues was also low after i.v. administration.
Docetaxel was more extensively distributed into cancer
tissues than paclitaxel after administration via both routes.
Moreover, we found that i.p. administration of docetaxel
rather than i.v. injection was pharmacokinetically superior
in the treatment of peritoneal dissemination of cancer
in mice [17, 19]. Docetaxel (8mg/kg) was intravenously
or intraperitoneally injected into athymic nude mice with
peritonealdisseminationofMKN-45Phumangastriccancer,
and we measured the concentration changes in plasma,
ascitic fluid, solid cancer tissue, and cancer cells suspended
in the peritoneal cavity (Figure 6). The drug concentration
in ascitic fluid was about 100-fold higher after i.p. injection
than after i.v. injection, while the plasma concentrations
were rather similar. In suspended free cancer cells in the
peritoneal cavity, the drug concentration was much higher
in the i.p. group than in the i.v. group, in parallel with
the concentrations in ascites after drug injection via these
routes. In the case of i.v. injection, the drug appeared rapidly
in solid cancer tissue and then the concentration gradually
decreased, followingthe change in the plasma concentration,
but the apparent cancer tissue to plasma concentration
ratio (Kp,app) was maintained at about 3 to 8 for 8h,
as observed in the AH130-bearing rat model (Figure 5).
Docetaxel concentration in solid cancer was maintained at
a higher level from 2h to 8h after i.p. injection as compared
withthatafteri.v.injection. Ontheotherhand,thedocetaxel
concentrations in normal organs rapidly decreased up to
1h and then gradually decreased in the i.v. group, while
in the i.p. group the concentrations increased up to 2 or
4h after injection and then slowly decreased [17]. Namely,
docetaxel injected into the peritoneal cavity was transferred
rather slowly to the peripheral blood flow; the ratio of
AUCp/AUCaafter i.p. injection of docetaxel was 0.071, but
when i.v. injected, the drug passed comparatively easily
into the peritoneal cavity from the blood flow; the ratio of
AUCa/AUCp after i.v. injection was 0.233 although it has
been reported the existence of a blood-peritoneal barrier
[2]. These results indicate that the i.p. injection of docetaxel
was considered to be advantageous as a treatment method
for peritoneal dissemination of cancers, offering higher local
drug concentration and low systemic toxicity compared with
i.v. injection.
4.Influence of SurfactantVehicleson
the Pharmacokinetic Behavior of Taxanes
Because paclitaxel and docetaxel have physicochemically
similar properties, the difference of distribution after admin-
istration of these drugs may be attributed largely to the
surfactant vehicles used to micellize and dissolve these drugs,
but not the properties of the drugs themselves. Taxane
anticancer drugs are commercially available as micellar
preparations, Taxol and Taxotere, which consist of paclitaxel
in crEL and docetaxel in PS-80, respectively. It has been
reported that surfactants increase cellular accumulation of
anticancerdrugsandmodulatethedrugresistanceofcancers
expressing P-glycoprotein [20, 21]. On the other hand,
crEL has been reported to inhibit the intestinal absorption
and tissue permeability of paclitaxel [22–25]. However, P-
glycoprotein is an efflux transporter in both multidrug-
resistant cells and small intestinal epithelium cells, and
therefore if these surfactants only inhibit the function of
P-glycoprotein, drug accumulation should increase. This
apparent contradiction may be explained as follows. CrEL
increased the sensitivity of multidrug-resistant cells to
daunorubicin at concentrations over 0.1μL/mL (0.01%)
and completely reversed the resistance at 2.0μL/mL (0.2%)
[26, 27]. PS-80 has also been shown to be a multidrug
resistance modulator in vitro at concentrations between 0.2
and 0.3μL/mL (0.02–0.03%) [21, 28] but was ineffective in
vivo, because of its very rapid clearance [27, 29]. Then, we
examined the influence of crEL and PS-80 on the in vitro
uptake of taxanes into AH130 cells, which do not express P-
glycoprotein [30]. The intracellular uptake of docetaxel and
paclitaxel decreased with increasing vehicle concentration
(Figure 7). When these drugs were dissolved in 0.0125%
ethanol (final concentration), the intracellular amounts of
these drugs were similar, but in the presence of surfactants
(at concentrations above 0.0125%) paclitaxel transport into
the cells was less than half that of docetaxel. CrEL and PS-
80 at concentrations above 0.5% both inhibited paclitaxel
entry into red blood cells, in a concentration-dependent
manner and with similar potency [18]. These results indicate
that both surfactants inhibit the plasma membrane perme-
ability at concentrations above 0.125%, although they can
modulate the P-glycoprotein-dependent drug transport at
lower concentrations. It is thought that the cell membrane

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6 Gastroenterology Research and Practice
Ascitic fluidPlasma
0.01
1
10
100
02468
Time (hr)
0.1
0.1
0.01
1
10
0.1
1
10
0
246
8
Time (hr)
Suspended cancerSolid cancer
0
2
4
6
02468
Time (hr)
02468
Time (hr)
Concentration (µg/mL)
Concentration (µg/mL)
∗
∗
∗
∗
∗
∗
∗
∗
∗
Concentration (µg/g tissue)
Concentration (ng/104cells)
Figure 6: Time courses of docetaxel concentration in plasma, ascetic fluid, solid cancer, and suspended free cancer cells after an i.v. or i.p.
injection of Taxotere in MKN-45P gastric cancer-bearing mice [17]. Taxotere (8mg/kg) was i.v. (open symbols) or i.p. (closed symbols)
injected into cancer-bearing mice on day 21 after i.p. inoculation of 107MKN-45P gastric cancer cells. Each point with bar represents the
mean ± SD of three mice.∗Significantly different from i.v. injection at P < 0.05.
DOC/crEL
DOC/PS
PAC/crEL
PAC/PS
0
0.2
0.4
0.6
0.8
1
1.2
0 0.01250.1250.25 0.51
Vehicle concentration (%)
Concentration (µg/4×106cells)
∗
∗
∗
∗∗
∗∗
∗
∗
∗
∗
∗
∗∗
∗
∗
Figure 7: Effects of surfactants on uptake of paclitaxel and docetaxel in AH130 cells. Cells were treated with 3μg/mL of docetaxel (DOC) or
paclitaxel (PAC) dissolved with 0.125% ethanol (0) or the indicated concentrations of crEL or PS-80 (PS) for 30min. The data at 0.0125%
concentration of these surfactants are taken from [15]. Each column with bar represents the mean ± SD of at least three experiments
performed in triplicate.∗,∗∗Significantly different from docetaxel at P < 0.05 and 0.01, respectively.
permeability of taxanes is determined by the degree of
affinity for, and the ease of dissociation from, surfactant
micelles [31]. Paclitaxel seems to be trapped in the surfactant
micelles more easily and binds to them more strongly than
docetaxel.
Next, we compared the influence of surfactants on the
in vivo pharmacokinetics of taxanes administered intraperi-
toneallytorats[18].Afterinjectionofpaclitaxelin4.2%crEL
into the peritoneal cavity, the permeation of paclitaxel into
the systemic circulation was very slow compared with that

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Gastroenterology Research and Practice7
100
0
20
40
60
80
0510152025303540 455055 60 65
Survival days
Survival rate (%)
Untreated control
Docetaxel in 1.5% PS-80
Docetaxel in 75% PS-80
Figure 8: Influence of PS-80 on the anticancer effect of docetaxel (1mg/kg) in AH130 tumor-bearing rats. AH130 tumor-bearing rats were
intraperitoneally administered 1mg/kg of docetaxel in a volume of 20mL of 1.5% or 7.5% PS-80 on day 0. N = 6.
Table 3: Pharmacokinetic parameters of paclitaxel (PAC) and docetaxel (DOC) in plasma and ascitic fluid after an i.p. administration of
drugs in crEL or PS-80 to nontumor rats [18].
ka AUCp
(mg∗hr/L)
18.4 ±3.3∗
6.93 ±1.32
8.59 ±1.23
11.4 ±1.1
AUCa
(mg∗hr/L)
8,870 ± 790∗
1,170 ± 120
3,520 ± 110
3,130 ± 320
Ratio of
AUCp/AUCa
0.00207 ± 0.00029∗
0.00592 ± 0.00153
0.00244 ± 0.00026
0.00364 ± 0.00026
(hr−1)
PAC in 4.2% crEL
DOC in 1.5% PS-80
DOC in 4.2% crEL
DOC in 7.5% PS-80
0.019 ±0.0018∗
0.394 ±0.021
0.165 ±0.004
0.130 ±0.005
The value of AUC was calculated from 0 to 24h after an i.p. administration of 40mg/kg of each drug.
ka: the apparent first-order absorption rate constant from the peritoneal cavity.
Each value represents the mean ± SD of three rats.
∗Significantly different from DOC in 1.5% PS-80 at P < 0.01.
of docetaxel in 1.5% PS-80. However, the permeation of
docetaxel from the peritoneal cavity to the peripheral blood
stream was markedly decreased by changing the surfactant
from 1.5% PS-80 to 4.2% crEL though it did not reach the
levelofpaclitaxelin4.2%crEL.vanTellingenetal.[29]noted
that PS-80 does not interfere with the disposition kinetics of
docetaxel. However, the peritoneal permeability of docetaxel
wasloweredbyincreasingtheconcentrationofPS-80to7.5%
(Table 3).
Thus, the disposition kinetics of paclitaxel is influenced
more strongly than that of docetaxel by micellar surfactants,
as the concentration is increased.
5.Influence of Surfactantson
the AnticancerEffect of Taxanes
Finally, we examined the influence of surfactants on the
anticancer effect of docetaxel after i.p. administration to
AH130-bearing rats. The anticancer effect of docetaxel
became less potent as the concentration of PS-80 was
increased (Figure 8). The surfactant not only decreased the
permeation of the taxane into the systemic circulation and
maintained a high concentration of the drugs in the peri-
toneal cavity (Table 2), but also inhibited the drug transport
into cancer cells, in a concentration-dependent manner,

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8 Gastroenterology Research and Practice
thereby reducing the anticancer effect. Similarly, it is thought
that the anticancer effect of paclitaxel is strongly influenced
by its vehicle, crEL, because the cell permeation of paclitaxel
is readily inhibited by surfactants. The antitumor potency of
Taxotere is known to be about 3 times that of Taxol. But, this
difference in the potency of these antitumor drugs may be
due largely to the difference in the kind and concentration
of micellar surfactants used. Moreover, it has been reported
that PS-80 is readily degraded by serum esterase [27, 29, 31],
while crEL is stable in the body [32]. Consequently, because
Taxotere readily releases docetaxel in the peritoneal cavity so
that it can rapidly permeate into the systemic circulation,
not only can docetaxel be directly transported into cancer
cells, but also the drug can be distributed to cancer cells
from the blood. This has been called the “sandwich effect”
of Taxotere or the dual anticancer effect of docetaxel [33].
Taxol, a paclitaxel formulation with crEL, hardly releases the
antitumor agent, so the distribution to tumors is small, and
the antitumor potency may be less than that of Taxotere.
6.Conclusion andPerspective
Though the chemical and physical properties of taxane anti-
cancer drugs, paclitaxel, and docetaxel are very similar, the
disposition kinetics of these drugs are markedly influenced
by their micellar surfactant vehicles after administration of
commercial preparations. To treat peritoneal dissemination
of cancers, i.p. administration seems logically preferable to
systemic administration. In fact, after i.p. administration of
commercialpreparationsdilutedwithphysiologicalsolution,
paclitaxel showed a much higher i.p. concentration and less
penetration into the systemic circulation than docetaxel.
Consequently, the anticancer effect of paclitaxel appears
to be stronger than that of docetaxel. However, actually
the opposite is the case because the cell permeability of
paclitaxel is significantly inhibited by surfactants. Taxol
is a micellar formulation of paclitaxel in crEL, of which
the content is much higher than in other crEL micellar
preparations [34]. Taxotere is a preparation of docetaxel
micellized with PS-80, which is rapidly degraded in the body
and readily releases the anticancer ingredient, as compared
with crEL. These characteristics seem to be the reasons why
the anticancer effect of Taxotere is more potent than that
of Taxol. Moreover, because many drugs are solubilized in
a micellar surfactant vehicle, such as crEL, pharmacokinetic
and pharmacodynamic drug-drug interactions may occur
when hydrophobic drugs are administered in combination
with an injection preparation containing a surfactant vehicle
[35]. Further, a preparation not containing crEL is desirable
to avoid hypersensitivity reaction. Recently, Abraxane has
been developed as a novel crEL-free nanoparticle albumin-
bound paclitaxel preparation. Data on the disposition kinet-
ics of paclitaxel after i.p. administration of the preparation
have not yet been reported and would be of consider-
able interest. Furthermore, hyperthermic intraperitoneal
chemoperfusion (HIPEC) has been developed for treatment
for peritoneal cancers with a variety of anticancer agents.
It will also be important to study the pharmacokinetics
of anticancer drugs in HIPEC to ensure safe and effective
treatment.
Conflict of Interests
The authors do not have any conflict of interests with the
content of the manuscript.
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