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Clinical Trials |
Department of Medical Oncology, Daniel den Hoed Kliniek, Rotterdam Cancer Institute and University Hospital Rotterdam, 3075 EA Rotterdam, the Netherlands
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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7 (up to 50 h) to 1 (at 500 h). This decrease
could be explained by the fact that glucuronidation of SN-38 and
bilirubin is increasingly competitive at lower drug levels. In
addition, no evidence was found for SN-38G transport through the Caco-2
cells. Our findings indicate that until now the circulation time of
SN-38 has been underestimated. This is of crucial importance to our
understanding of the clinical action of CPT-11 and for future
pharmacokinetic/pharmacodynamic relationships. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1; no
previous treatment with antineoplastic agents for at least 4 weeks (or
6 weeks in case of nitrosoureas or mitomycin C); no prior treatment
with CPT-11 or other topoisomerase I inhibitors; adequate hematopoietic
(WBC count >3.0 x 109/liter, absolute
neutrophil count >2.0 x 109/liter, and
platelet count >100 x 109/liter), renal
(serum creatinine concentration 135 µM or creatinine
clearance 
60 ml/min) and hepatic function (total serum bilirubin
1.25 x upper normal limit, and ASAT and ALAT concentrations
3.0 x upper normal limits); and no unresolved bowel obstruction
or chronic colic disease. The current clinical protocol was approved by
the Rotterdam Cancer Institute Review Board, and all patients signed
informed consent before study entry. Vials that contained 40 or 100 mg of CPT-11 (as a hydrochloride trihydrate form) formulated as a concentrated sterile solution (active drug concentration, 20 mg/ml) in d-sorbitol and a lactic acid-sodium hydroxide buffer system of pH 3.5–4.5 were provided by Rhône-Poulenc Rorer (Antony Cedex, France). The CPT-11 dose of 350 mg/m2 was administered as a 90-min i.v. infusion, after dilution of the pharmaceutical preparation in 250 ml of isotonic sodium chloride. In all patients, premedication consisted of 8 mg of ondansetron i.v. combined with 10 mg of dexamethasone i.v., administered 30 min before the start of chemotherapy.
Sample Collection and Handling.
Blood samples for pharmacokinetic analysis were drawn from a vein in
the arm opposite to that used for drug infusion and collected in 10-ml
glass tubes containing lithium heparin as anticoagulant. Samples were
obtained at the following time points: before drug administration; at
0.5, 1, and 1.5 h during infusion; and 0.17, 0.33, 0.5, 1, 1.5, 2,
4, 5, 8.5, 24, 32, 48, 56, 196, 360, and 504 h after the end of
infusion. Blood was immediately processed to plasma by centrifugation
for 5 min at 2500 rpm (4°C), which was then stored at -80°C until
the time of analysis (see below). A pretreatment feces sample was
collected from all patients 1 day prior to drug administration in a
polystyrene container and stored immediately at -80°C. After
thawing, these samples were homogenized individually on ice (at 0°C)
to prevent enzyme degradation in one or two volumes of a 0.1
M sodium acetate buffer (pH 7.0), depending on the water
content of the sample, using an Ultra-Turrax T25 homogenizer
(IKA-Labortechnik, Dottingen, Germany). The homogenates were
centrifuged for 5 min at 15,000 rpm, and the clear supernatants were
diluted 1-fold with 50% glycerol in water (v/v). The dilutions were
stored at -80°C until analysis for ß-glucuronidase activity (see
below).
Drug Analysis.
Pure reference standards of CPT-11 hydrochloride trihydrate (batch,
KO16), and the metabolites SN-38G trifluoroacetate (batch, YEO265), NPC
trifluoroacetate (batch, YEO304), and SN-38 hydrochloride (batch,
LIE783) were kindly provided by Rhône-Poulenc Rorer and were used
as received. Drug concentrations in plasma were determined as the total
of lactone and carboxylate forms by a validated HPLC method with
fluorescence detection as described previously (20)
. This
method was further modified, as reported, to allow determinations of
SN-38 and SN-38G at the low femtomol level (21)
. Because
of straying fluorescence characteristics, an incomplete extraction, and
the compound’s low relative retention on the reversed-phase HPLC
column (Hypersil ODS with 5 µm particles), the unchanged parent drug
could not be detected with this latter method (21)
.
Likewise, attempts to separately measure SN-38 lactone levels and
lactone to total ratios of SN-38 with similar sensitivity
characteristics as described above for SN-38 total drug
(21)
have not yet been successful because of interference
from endogenous plasma constituents.
Pharmacokinetic Analysis.
Individual plasma concentrations of CPT-11 and its metabolites were
fitted to a three-compartment model using the Siphar version 4.0
software package (SIMED, Créteil, France), as described
(18)
. The rate constants of the various disposition phases
and the AUC were estimated with a weighted-least squares method
(weighting factor, 1/y) using the fitted model, whereas the
total plasma clearance of CPT-11 was calculated by dividing dose
(expressed in mg base equivalents per squared meter of body surface
area) and the observed AUC. The Cmax
values (peak drug level) were determined graphically (as observed
values) in a concentration-time scatter plot. Metabolic ratios were
calculated as defined (22)
and included the relative
extent of conversion of CPT-11 to SN-38 (i.e.,
AUCSN-38:AUCCPT-11)
and the relative extent of glucuronidation of SN-38 (i.e.,
AUCSN-38G:AUCSN-38).
The latter was also evaluated as a function of time after drug
administration. The systemic SN-38 glucuronidation rate in individual
patients was estimated by calculation of the biliary index values
(23)
, expressed as AUCCPT-11
x
(AUCSN-38:AUCSN-38G).
Measurement of Fecal ß-Glucuronidase Activity.
The enzyme activity was determined by a miniaturized colorimetric assay
using phenolphthalein glucuronic acid as an artificial substrate, based
on a procedure described for ß-glucuronidase in bile of mini pigs
(24)
. Briefly, 20-µl sample aliquots of feces homogenate
were mixed with 20 µl of 0.1 M sodium acetate buffer (pH
7.0) containing 0.2% (w/v) BSA and 10 µl of the same buffer in the
presence of 0.03 M phenolphthalein glucuronic acid
(Sigma-Aldrich Co., Zwijndrecht, the Netherlands) and incubated for
1 h at 37°C in a shaking water bath. The enzymatic reaction was
terminated by the addition of 200 µl of 0.1 M sodium
phosphate buffer (pH 12.0), and the reaction product phenolphthalein
was determined by measurement of the absorbance at 550 nm against a
reagent blank on a Bio-Rad Model 550 automated microplate reader
(Bio-Rad Laboratories, Hercules, CA). A calibration standard curve of
phenolphthalein was constructed on the day of analysis, and
concentration versus absorbance data were fitted by linear
regression analysis. The mean regression equation had slope and
y-intercept values of 0.292 ± 0.021 and -0.004 ± 0.013 (n = 15), respectively, with a Pearson’s
moment correlation coefficient >0.9943. Enzyme activity levels in
unknown feces samples were calculated in triplicate using interpolation
of the corresponding regression analysis and expressed as micrograms of
phenolphthalein liberated per h at 37°C per milligrams of feces based
on dry-weight measurements (µg/h/mg). A formal method validation was
performed as described (25)
by replicate analysis of
quality control samples spiked to contain three different
concentrations on several occasions in the presence of a duplicate
7-point calibration curve and reference samples containing 1.6 units/h
of lyophilized type IX-A ß-glucuronidase (EC 3.2.1.31) from
Escherichia coli (Sigma Chemical Co., St. Louis, MO)
dissolved in 50% glycerol in 0.1 M sodium
acetate buffer (v/v). The within-run and between-run precision, as
determined by one-way ANOVA, ranged from 2.18 to 3.55% and 2.84 to
4.89% (n = 22 at each of the concentrations),
respectively, with a mean percentage deviation from nominal values of
less than ±6.14% for phenolphthalein data and ±3.30% for the
ß-glucuronidase reference standard.
In Vitro Metabolism of CPT-11 and NPC.
Biotransformation of CPT-11 and NPC into SN-38 was studied in freshly
prepared aliquots of human plasma, following a 5-min centrifugation
step at 3000 x g of whole blood samples obtained from
healthy volunteers. Prior to incubation, plasma samples were placed in
a shaking water bath at 37°C for 5 min. Aliquots of 50 µl of the
lactone forms of CPT-11 and NPC (from stock solutions containing 1.00
and 1.77 mg/ml in DMSO, diluted in a mixture of methanol-0.01
M hydrochloric acid) were then added to 450 µl
of plasma to yield the desired final concentrations (0.2 to 200
µM), followed by slight agitation by vortex mixing. To
determine the reaction velocity (i.e., V
expressed in nM/h/l of plasma), sample aliquots were taken
at a fixed time interval of 24 h, which was determined in
preliminary experiments to be sufficiently long to achieve steady-state
(not shown), and analyzed for the presence of total SN-38 as described
above for plasma samples. The Michaelis-Menten kinetics of the maximum
process rate (i.e., Vmax)
and the drug concentration associated with 0.5 x
Vmax (i.e.,
Km) were determined by a nonlinear
regression analysis implemented on the Number Cruncher Statistical
System software package (version 5.X; Jerry Hintze, East
Kaysville, UT, 1992).
Drug Transport by Caco-2 Cells.
The human colon adenocarcinoma cell line Caco-2 (American Type Culture
Collection, Rockville, MD) was grown as monolayers in DMEM containing
10% heat-inactivated fetal bovine serum, 100 µg/ml penicillin and
streptomycin, and 2 mM freshly added
L-glutamine (all from Life Technologies, Inc., Breda, the
Netherlands) according to procedures recommended by the American Type
Culture Collection. Cells were grown at 37°C in a humidified
atmosphere in 5% CO2/95% air as stock cultures
in 75-cm3
flasks and split at 80% confluency
using trypsin-EDTA. Caco-2 cells were then seeded at a density of
2.5 x 104
cells/insert in Transwell 12-well
plates containing 1-cm2
permeable polycarbonate
inserts with a 0.4-µm pore size (Costar Corp., Cambridge, MA). The
Caco-2 cells were maintained to monolayer growth by medium change every
3 days, until use in transport experiments at 28 days after seeding.
The apical side of the cell layer (insert) contained 0.5 ml, whereas
the basolateral side (well) contained 1.5 ml. Transport studies were
initiated with CPT-11, SN-38, and SN-38G [all dissolved in a mixture
of methanol-0.01 M hydrochloric acid (1:1, v/v) and diluted
further in medium at final concentrations of 1.7 and 17
µM (CPT-11), 2.5 and 25 µM (SN-38), and 1.5
µM (SN-38G), respectively], added to either the apical
or basolateral side. The final concentration of methanol in the dosing
medium was always <1%. At the end of the experiment (1, 2, 6, or
24 h continuous exposure times), the entire apical and basolateral
side solutions were collected separately in 1.5-ml polypropylene tubes
(Eppendorf, Hamburg, Germany) and then centrifuged for 5 min at 15,000
rpm (4°C) to remove residual particulate matter. The supernatants
were transferred to clean tubes and immediately stored at -80°C
until analysis by HPLC as described (20)
. Mean transport
fractions were calculated as the fraction of the total drug transported
after exposure.
The ß-glucuronidase content in the Caco-2 cells was measured using the phenolphthalein assay as described above for feces samples (detection limit, 0.3 µg/h/mg of protein), and total protein levels with the Coomassie-brilliant blue G-250 assay (26) .
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RESULTS |
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2 (on a 4-point scale according to National Cancer Institute
Common Toxicity Criteria version 2.0) was encountered in only three
patients (20%). Gastrointestinal toxicity was most prominent among
nonhematological side effects, with diarrhea graded 2 occurring in
eight patients (53%) and graded 3 in only 1 patient. One patient
developed severe liver dysfunction immediately after CPT-11
administration, with total bilirubin levels rising to levels >250
µM within 200 h and ASAT graded 3. This patient died
eventually 9 days after CPT-11 administration after experiencing grade
4 leukocytopenia, grade 4 neutropenia, and grade 4 diarrhea. Autopsy
revealed an obstructed biliary tree by pigment stones.
Pharmacokinetics.
The plasma concentration-time profiles of SN-38 after CPT-11 treatment
were very similar for all patients studied (displayed in Fig. 1
). In line with previous findings
(18
, 22)
, plasma concentrations gradually increased to
reach peak levels within 1.5–3 h after start of the i.v.
administration and slowly began to decline thereafter. SN-38
concentrations still remained detectable at 500 h after drug
administration [lower limit of quantitation of the HPLC assay, 13
pM (21)
]. As a result, values for
AUC0-inf and
T1/2 were significantly higher as
compared with estimates based on standard sampling time periods (Table 1)
. SN-38G was the principal metabolite
of CPT-11 (detected in plasma of most patients), with an estimated
T1/2 slightly decreased as compared
with unconjugated SN-38. The time profile of the molar concentration
ratios of SN-38G and SN-38 was also relatively consistent between
patients (Fig. 2)
, showing peak values at
6 h and a gradual decrease toward the end of the sampling time
period. Data obtained from the patient with liver dysfunction and
biliary obstruction showed aberrant pharmacokinetic profiles (Fig. 3)
, with substantially increased plasma
concentrations of both SN-38G and SN-38.
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The potential of oxidative metabolites of CPT-11 taking part in the
overall production of SN-38 was evaluated in experiments in freshly
prepared human plasma at fixed concentrations of NPC and CPT-11
(17)
. The formation of SN-38 from NPC and CPT-11 by serum
CE is shown in Fig. 4
. For NPC, the mean
values of Km and
Vmax obtained using the
Michaelis-Menten equation were 74 µM and 76
pmol/h/ml plasma, respectively, which is within the same range as
described for this conversion previously in an experimental setting
using human liver microsomes or purified hepatic CE (17)
.
We also confirmed the possibility of CPT-11 transformation to SN-38 in
human plasma with Km and
Vmax values of 126
µM and 52 pmol/h/ml plasma, respectively, which
agree very well with data of a previous study (27)
.
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DISCUSSION |
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2-fold increased as compared with estimates reported in earlier
studies (18
, 22)
. In addition, we found that the
SN-38-G:SN-38 plasma concentration ratio decreases in time from 7
(at 50 h) to 1 (at 500 h). These data not only emphasize
the need to apply appropriate kinetic models with sufficient sampling
time points for the accurate estimation of complete concentration-time
profiles but may also have direct significant clinical relevance in
view of the fact that relationships between drug exposure and effect
(i.e., toxicity and efficacy) are still poorly defined.
Several possible explanations can account for the increase in
disposition half-life of SN-38 and the time-varying SN-38G:SN-38
concentration ratios after i.v. administration of CPT-11. Previously,
biliary secretion of CPT-11, SN-38, and SN-38G has been described and
quantitated in a rat model, whereas intestinal reabsorption of biliary
secreted radioactivity in that same study already suggested
recirculation of at least some of the compounds (31)
.
This, in combination with numerous clinical data, has led to the
proposed enterohepatic recirculation of CPT-11 and its metabolites. It
has been suggested in clinical studies that the enterohepatic
recirculation is so prominent that its effects can be measured in the
systemic circulation by a short rise of concentration of SN-38 at 8
h after i.v. administration of CPT-11 (23)
. As described
in earlier reports (18
, 32)
and again in this study, we
could not confirm a consistent rise in the SN-38 plasma concentration
shortly after systemic drug exposure. Direct proof of a recirculation
process of any of the compounds has, to our knowledge, not yet been
published. For this reason, we investigated the intestinal absorption
and transepithelial flux of CPT-11, SN-38, and SN-38-G in
vitro in Caco-2 cell monolayers, an established model of human
intestinal drug absorption resembling the small bowel. In these
in vitro experiments, we found a time and
concentration-dependent transport fraction for both CPT-11 and SN-38.
Although the transport fractions from basolateral to apical were higher
as compared with that from apical to basolateral, it is still possible
that in vivo transport from the intestinal lumen to the
circulation of CPT-11 and SN-38 is of clinical relevance, especially
when intraluminal concentration of either one of the compounds is
relatively high. SN-38G on the other hand could not be transported from
the apical to basolateral side, consistent with its increased aqueous
solubility resulting from the highly polar nature of the glucuronic
acid group. In addition, the difference in absorption pattern between
SN-38 and SN-38G is in accordance with the decreasing SN-38G:SN-38
ratio in time. Furthermore, we could not detect SN-38 after exposure of
SN-38G in any compartment of this model, consistent with the
undetectable levels of ß-glucuronidase activity in the Caco-2 cells.
There was also no metabolism of CPT-11 in the Caco-2 cells, despite the
fact that cytochrome P-450 3A4, the major isoform in the human
intestine (33
, 34)
, has been indicated to be present at
low levels in the Caco-2 cell line (35)
. To further
examine the potential contribution of cytochrome P-450 3A4, if any, to
the transport of CPT-11 using the Caco-2 cell system, experiments using
cells with increased expression of this isozyme induced with addition
of 1
,25-dihydroxyvitamin D3 (36)
to the growth medium are currently under investigation.
Because we found a concentration-dependent uptake of SN-38 in the above-described model, high fecal SN-38 concentrations can be of clinical significance, in a sense that a potential recycling of SN-38 reduces the effective clearance and may add a distributional compartment by way of the enteric circuit. Many glucuronides are susceptible to the effects of enterohepatic recirculation after hydrolysis through the action of bacterial and enteric ß-glucuronidases (37) . Indeed, conversion of SN-38G to SN-38 by bacterial intestinal ß-glucuronidase has been shown to occur in animal models (38) as well as in humans (18) . In addition, high intraluminal concentrations of SN-38 in combination with prolonged retention and subsequent structural and functional injuries to the intestinal tract is considered to be one of the mechanisms underlying the late-onset form of intestinal toxicity encountered in patients treated with CPT-11 (39) . To assess the importance of SN-38G deconjugation with respect to potential SN-38 recycling, we therefore also evaluated the levels of ß-glucuronidase activity in fecal pretreatment specimens of individual patients. Interpatient enzyme activity varied up to a 100-fold and did not correlate with any of the plasma pharmacokinetic parameters of SN-38. Overall, this finding shows very clearly that interindividual variation in this enzyme is unimportant in explaining SN-38 pharmacokinetic variability. This is also consistent with our recent observation that modulation of fecal ß-glucuronidase activity by neomycin coadministration has no significant influence on systemic (plasma) concentrations of SN-38 (40) . A potential approach for reducing CPT-11-induced intestinal toxicity may therefore be to reduce bacterial ß-glucuronidase-mediated deconjugation of SN-38G to limit local accumulation of SN-38 and subsequent mucosal destruction. A clinical trial to evaluate the toxicological consequences of pretreatment with neomycin before the administration of CPT-11 is in progress.4 The paradox between the concentration-dependent absorption process of SN-38 in the Caco-2 cells and the lack of relationship of fecal ß-glucuronidase activity with SN-38 pharmacokinetics is presumably caused by the lack of enzyme activity in the luminal contents of the entire small intestine, where reabsorption of drug is most likely to occur (39) .
Another possibility that could lead to prolongation of the terminal
disposition phase of SN-38 is its continuous formation out of the
oxidative metabolites of CPT-11. In an in vitro model,
conversion of APC to SN-38 by rabbit liver CE has been described
(41)
. However, rabbit liver CE, although very similar to
human liver CE with respect to amino acid sequence, is 100-fold more
efficient in activating APC then the human enzyme in vitro
(42)
. Indeed, in vitro conversion of APC to
SN-38 by human CE or human liver microsomes could not be demonstrated
(16)
, suggesting that APC is not a prodrug of SN-38 in
humans. NPC, on the other hand, could be metabolized into SN-38
in vitro by human liver microsomes and human liver CE to
SN-38 after enzymatic cleavage of the
4-N-(1-piperidino)-1-amino group at C10 (17)
.
We have reported recently that peak plasma concentrations and AUC
values of NPC are very low after CPT-11 administration
(32)
, which could point to rapid and virtually complete
conversion of this compound to SN-38 in the systemic circulation. To
test this possibility, we evaluated the in vitro production
of SN-38 from NPC and CPT-11 in freshly prepared human plasma and found
substantial formation from both compounds. These data appear to
indicate that this metabolic pathway is underestimated in relationship
to what extent it adds to the total amount of SN-38 formed. Although
this route could clearly contribute to the prolonged disposition phase
of SN-38 and may be an important determinant of the substantial
interpatient variability in CPT-11 pharmacokinetics observed here and
elsewhere (32)
, the overall quantitative aspects of this
source of SN-38 remain unknown.
Another potential contributing factor to the prolonged circulation time of SN-38 may come from competitive binding of SN-38 and bilirubin to UDP glucuronosyltransferases (43) . Thus, in the lower concentration regions of SN-38, competitive binding with bilirubin may inhibit glucuronidation and prolong circulation times of the active metabolite. Although we do not have direct proof for this mechanism in the clinical situation, it is known that even minor liver enzyme disturbances and/or slight hyperbilirubinemia can give significant rise in both hematological and intestinal toxicity (44, 45, 46) . In patients with (slightly) elevated bilirubin levels, competitive binding will influence the early plasma SN-38 concentration only to a minor extent but will give a disproportional prolongation of the terminal disposition phase of SN-38 and is thus likely to affect SN-38G:SN-38 concentration ratios. The importance of this competitive interaction between SN-38 and bilirubin is further underscored by our observations made in a single patient who developed very severe toxicity. This patient developed liver failure during treatment with CPT-11 accompanied with a dramatic rise in serum bilirubin concentrations. Compared with other patients, this patient experienced at least a 10-fold increase in the SN-38 plasma concentrations, which is in accordance with this hypothesis and consistent with other published data indicating substantial increases in systemic exposure to CPT-11 and SN-38 in patients with liver dysfunction (45) .
In addition to the processes mentioned, a variety of other factors may influence SN-38 pharmacokinetics, including binding of the compound to plasma proteins [principally human serum albumin and gamma globulin (18) ]. It has been well established that for drugs with very high protein binding [e.g., SN-38, which is 94–96% bound (47) ], prolonged sampling may demonstrate a relatively slow redistribution of drug into plasma and thus prolong the apparent half-life. For drugs undergoing enterohepatic recirculation (e.g., SN-38), the times that patients ingest food may also impact upon plasma drug concentrations. However, although the times that the patients under study took any food were not noted and its potential impact on kinetics were not investigated here, a previous clinical study with the related compound topotecan has shown that food intake does not affect the extent of drug absorption (48) .
In conclusion, we have shown by applying an extended sampling time period of 500 h that until now the circulation time of SN-38 in cancer patients treated with CPT-11 has been greatly underestimated. Because of the poorly defined relationships between pharmacokinetic parameters and pharmacodynamic outcome of CPT-11 treatment, the presently observed prolonged terminal disposition phase of SN-38 should be taken into consideration in future studies attempting to identify kinetic correlates that would assist in prediction of both hematological and intestinal toxicity. Further investigation to reveal the clinical importance of our findings is clearly warranted.
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FOOTNOTES |
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1 This work was presented previously in part at
the AACR-NCI-EORTC International Conference on Molecular Targets and
Cancer Therapeutics: Discovery, Development, and Clinical Validation,
November 16–19, 1999, Washington, D. C. 
2 To whom requests for reprints should be
addressed, at Department of Medical Oncology, Rotterdam Cancer
Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam,
P. O. Box 5201, 3008 AE Rotterdam, the Netherlands. Phone:
31-10-4391112; Fax: 31-10-4391053; E-mail: sparreboom{at}onch.azr.nl
3 The abbreviations used are: CPT-11, irinotecan;
CE, carboxylesterase; SN-38, 7-ethyl-10-hydroxycamptothecin; SN-38G,
7-ethyl-10-[3,4,5-trihydroxy-pyran-2-carboxylic acid]camptothecin
(the ß-glucuronic acid conjugate of SN-38); APC,
7-ethyl-10-[4-N-(5-aminopentanoic
acid)-1-piperidino]carbonyloxycamptothecin; NPC,
7-ethyl-10-[4-(1-piperidino)-1-amino]carbonyloxycamptothecin;
AUC, area under the concentration-time curve; HPLC, high-performance
liquid chromatography; ASAT, aspartate aminotransferase; ALAT, alanine
aminotransferase.
4 D. F. S. Kehrer and A. Sparreboom, unpublished
data.
Received 2/ 4/00; revised 4/ 4/00; accepted 4/ 7/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,25-dihydroxy-vitamin D3. Mol. Pharmacol., 51: 741-754, 1997.This article has been cited by other articles:
|
|
 |
|
  M. N. Tallman, K. K. Miles, F. K. Kessler, J. N. Nielsen, X. Tian, J. K. Ritter, and P. C. Smith The Contribution of Intestinal UDP-Glucuronosyltransferases in Modulating 7-Ethyl-10-hydroxy-camptothecin (SN-38)-Induced Gastrointestinal Toxicity in Rats J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 29 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Michael, M. Thompson, R. J. Hicks, P. L. Mitchell, A. Ellis, A. D. Milner, J. Di Iulio, A. M. Scott, V. Gurtler, J. M. Hoskins, et al. Relationship of Hepatic Functional Imaging to Irinotecan Pharmacokinetics and Genetic Parameters of Drug Elimination J. Clin. Oncol., September 10, 2006; 24(26): 4228 - 4235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Brandi, J. Dabard, P. Raibaud, M. Di Battista, C. Bridonneau, A. M. Pisi, A. M. M. Labate, M. A. Pantaleo, A. De Vivo, and G. Biasco Intestinal Microflora and Digestive Toxicity of Irinotecan in Mice Clin. Cancer Res., February 15, 2006; 12(4): 1299 - 1307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Michael, M. Brittain, J. Nagai, R. Feld, D. Hedley, A. Oza, L. Siu, and M. J. Moore Phase II Study of Activated Charcoal to Prevent Irinotecan-Induced Diarrhea J. Clin. Oncol., November 1, 2004; 22(21): 4410 - 4417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Paoluzzi, A. S. Singh, D. K. Price, R. Danesi, R. H. J. Mathijssen, J. Verweij, W. D. Figg, and A. Sparreboom Influence of Genetic Variants in UGT1A1 and UGT1A9 on the In Vivo Glucuronidation of SN-38 J. Clin. Pharmacol., August 1, 2004; 44(8): 854 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Sanghani, S. K. Quinney, T. B. Fredenburg, W. I. Davis, D. J. Murry, and W. F. Bosron HYDROLYSIS OF IRINOTECAN AND ITS OXIDATIVE METABOLITES, 7-ETHYL-10-[4-N-(5-AMINOPENTANOIC ACID)-1-PIPERIDINO] CARBONYLOXYCAMPTOTHECIN AND 7-ETHYL-10-[4-(1-PIPERIDINO)-1-AMINO]-CARBONYLOXYCAMPTOTHECIN, BY HUMAN CARBOXYLESTERASES CES1A1, CES2, AND A NEWLY EXPRESSED CARBOXYLESTERASE ISOENZYME, CES3 Drug Metab. Dispos., May 1, 2004; 32(5): 505 - 511. [Abstract] [Full Text] [PDF]
|
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|
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|
|
H. Jinno, M. Saeki, Y. Saito, T. Tanaka-Kagawa, N. Hanioka, K. Sai, N. Kaniwa, M. Ando, K. Shirao, H. Minami, et al. Functional Characterization of Human UDP-Glucuronosyltransferase 1A9 Variant, D256N, Found in Japanese Cancer Patients J. Pharmacol. Exp. Ther., August 1, 2003; 306(2): 688 - 693. [Abstract] [Full Text] [PDF]
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J. D. Chester, S. P. Joel, S. L. Cheeseman, G. D. Hall, M. S. Braun, J. Perry, T. Davis, C. J. Button, and M. T. Seymour Phase I and Pharmacokinetic Study of Intravenous Irinotecan Plus Oral Ciclosporin in Patients With Fluorouracil-Refractory Metastatic Colon Cancer J. Clin. Oncol., March 15, 2003; 21(6): 1125 - 1132. [Abstract] [Full Text] [PDF]
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H. Jinno, T. Tanaka-Kagawa, N. Hanioka, M. Saeki, S. Ishida, T. Nishimura, M. Ando, Y. Saito, S. Ozawa, and J.-i. Sawada Glucuronidation of 7-Ethyl-10-hydroxycamptothecin (SN-38), an Active Metabolite of Irinotecan (CPT-11), by Human UGT1A1 Variants, G71R, P229Q, and Y486D Drug Metab. Dispos., January 1, 2003; 31(1): 108 - 113. [Abstract] [Full Text] [PDF]
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R. Xie, R. H.J. Mathijssen, A. Sparreboom, J. Verweij, and M. O. Karlsson Clinical Pharmacokinetics of Irinotecan and Its Metabolites: A Population Analysis J. Clin. Oncol., August 1, 2002; 20(15): 3293 - 3301. [Abstract] [Full Text] [PDF]
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D. F.S. Kehrer, R. H.J. Mathijssen, J. Verweij, P. de Bruijn, and A. Sparreboom Modulation of Irinotecan Metabolism by Ketoconazole J. Clin. Oncol., July 15, 2002; 20(14): 3122 - 3129. [Abstract] [Full Text] [PDF]
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N. Hanioka, S. Ozawa, H. Jinno, T. Tanaka-Kagawa, T. Nishimura, M. Ando, and J.-i. Sawada Interaction of Irinotecan (CPT-11) and Its Active Metabolite 7-Ethyl-10-Hydroxycamptothecin (SN-38) with Human Cytochrome P450 Enzymes Drug Metab. Dispos., April 1, 2002; 30(4): 391 - 396. [Abstract] [Full Text] [PDF]
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K. Sai, N. Kaniwa, S. Ozawa, and J.-i. Sawada A New Metabolite of Irinotecan in Which Formation Is Mediated by Human Hepatic Cytochrome P-450 3a4 Drug Metab. Dispos., November 1, 2001; 29(11): 1505 - 1513. [Abstract] [Full Text] [PDF]
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R. H. J. Mathijssen, R. J. van Alphen, J. Verweij, W. J. Loos, K. Nooter, G. Stoter, and A. Sparreboom Clinical Pharmacokinetics and Metabolism of Irinotecan (CPT-11) Clin. Cancer Res., August 1, 2001; 7(8): 2182 - 2194. [Abstract] [Full Text] [PDF]
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D. F. S. Kehrer, A. Sparreboom, J. Verweij, P. de Bruijn, C. A. Nierop, J. van de Schraaf, E. J. Ruijgrok, and M. J. A. de Jonge Modulation of Irinotecan-induced Diarrhea by Cotreatment with Neomycin in Cancer Patients Clin. Cancer Res., May 1, 2001; 7(5): 1136 - 1141. [Abstract] [Full Text]
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), SN-38 (
) (all left y-axis) and
total bilirubin (, dotted line; right
y-axis) in a single patient with progressively impaired liver
function treated with a 90-min i.v. infusion of CPT-11 at a dose level
of 350 mg/m2.