JP2002518332A - Administration method of camptothecin compound for cancer treatment with reduction of side effects - Google Patents

Abstract

  (57) [Summary] A method of administering a camptothecin compound, such as irinotecan hydrochloride, for reducing side effects of diarrhea, and a method of treating cancer and AIDS with a camptothecin compound, which comprises administering the camptothecin compound while maintaining the small intestinal lumen and bile at an alkaline pH.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD [0001] The present invention relates to camptothecin compounds, particularly irinotecan hydrochloride composition formulations and methods of administering camptothecin compounds such as irinotecan hydrochloride for the treatment of cancer and AIDS with reduced side effects.

BACKGROUND OF THE INVENTION [0002] Camptothecins are known as Chinese Canptotheca tree and Asian no
It is a quinoline-based alkaloid found in the bark of the thapodytes tree.
It is composed of aminocamptothecin, CPT-11 (irinotecan), DX-895
Closely related to 1F and topotecan. These compounds are useful for treating breast, ovarian, colon, malignant melanoma, small cell lung cancer, thyroid cancer, lymphoma and leukemia. These compounds are also used for treating AIDS.

Irinotecan hydrochloride (CPT-11) (4S) -4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy] -1H-pyrano [3 ′, 4 ′ : 6,7] indolizino [1,2-b] quinoline-3,14 (4
(h, 12H) dione hydrochloride has a novel mechanism of antitumor activity, ie, suppression of DNA topoisomerase I. Topoisomerase is the DNA that makes up the chromosome
It is an enzyme that winds and unwinds. Since chromosomes must be unwound to make proteins, camptothecin compounds tightly wind chromosomes so that they cannot make proteins. Because cancer cells grow at a much faster rate than normal cells, they are more vulnerable to topoisomerase suppression than normal cells.

[0004] CPT-11 has shown clinically effective antitumor activity (2,3), and recently C
The survival effect of PT-11 was shown in colorectal cancer. However, it has great toxicity in clinical practice: leukopenia and diarrhea. Clinical use of CPT-11 at high doses is associated with an unexpected and significant incidence of diarrhea (4
, 6, 7, 12), diarrhea is now recognized as the dose limiting toxicity of this drug (4).
~ 7). Numerous pharmacokinetic analyzes showing large inter-patient variability have been performed to predict the incidence of diarrhea, but there are some conflicting results (8-11).
.

[0005] CPT-11 and its metabolites SN-38 and SN-38-Glu
Was detected in human bile as well as in human plasma. Of the three compounds, S
N-38 has strong cytotoxicity and is a glucuronidated form of SN-38, SN
-38-Glu is inactivated and CPT-11 has significantly less cytotoxicity compared to SN-38. These compounds have an α-hydroxy-3-lactone ring, which undergoes reversible hydrolysis mainly at a rate dependent on pH (15, 16, 1).
7). At pH above physiological pH, the lactone form is unstable and equilibrium favors hydrolysis to open the lactone ring, yielding the carboxylate form. Under acidic conditions, the reverse reaction with formation of the lactone is advantageous. A similar reaction is CPT-11.
And also occurs with SN-38-Glu.

[0006] Several reports suggest that the major metabolic pathways in humans are as follows; CPT-11 is the active metabolite, 7-ethyl-10-hydroxy-, mainly due to carboxylesterases of hepatic origin. It is hydrolyzed to camptothecin (SN-38). Some of SN-38 are subsequently bound by the liver enzyme UDP-glucuronyltransferase to form SN-38β-glucuronide (SN-38).
38-Glu) and is excreted in bile together with other components CPT-11 and SN-38 (13, 14). The three compounds are thought to be reabsorbed by the small intestine cells and enter the enterohepatic circulation. Recently, the liver cytochrome P-450 3A enzyme converts CPT-11 to 7-ethyl-, which has 500 times less antitumor activity than SN-38.
It was found to be metabolized to 10- [4-N- (5-aminopentanoic acid) -1-piperidino] carbonyloxycamptothecin (Rivory et al., 1996b; Ha
az et al., 1997). CPT-11, SN-38 and SN38-Glu are α-
It has a hydroxy-3-lactone ring, which undergoes reversible hydrolysis primarily at a rate dependent on pH (Fassbery et al., 1992). Above physiological pH, the lactone form is unstable and equilibrium favors hydrolysis towards opening the lactone ring and producing the carboxylate form. Under acidic conditions, the lactone-carboxylate conversion changes to the lactone form. CPT-11, SN-38 and SN38-Glu are excreted in bile and are released together with it into the small intestinal lumen (Atsumi et al., 1991; Lokie
c et al., 1995; Chu et al., 1997a, b). In addition, to a lesser degree (Atsumi et
al., 1995), an additional pathway is in which CPT- from serum into the lumen through small intestinal epithelial cells.
11 and its metabolites. Once in the small intestine, SN38-Gl
u is decoupled to SN-38 by bacterial β-glucuronidase in the cecum and colon (Takatsuna et al., 1996). CPT-11, SN-38 and SN38-
It is believed that Glu is reabsorbed to some extent by small intestinal cells and enters the enterohepatic circulation.

[0007] To date, there is little information about the intestinal uptake and transport mechanisms of CPT-11 and its derivatives. This knowledge is a critical step in understanding the mechanism by which CPT-11 induces diarrhea. In this study, the uptake of CPT-11 and SN-38 by small intestinal epithelial cells was estimated and their respective effects on cytotoxicity were correlated.

[0008] The structures of some camptothecin derivatives are known.

[0009]

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[0010] Further, US Pat. No. 5,552,154 discloses that camptothecin (CPT) and its derivatives in the form of a closed lactone ring are administered intramuscularly or predominantly. In such cases, a wide range of global remissions of human cancer could be obtained without the toxicity previously observed with CPT Na ⁺ . The derivatives of CPT used were 9-amino-20 (S) -camptothecin (9AC), 9-nitro-20 (S
) - it was a camptothecin (9NO _2).

[0011] US Pat. No. 5,468,754 states that CPT 11 and other camptothecin derivatives undergo an alkaline pH-dependent hydrolysis of E-ring lactones. The slow rate of the reaction allows one to assess whether both the lactone and non-lactone forms of the drug stabilize the topoisomerase-cleaved DNA complex. Studies show that only the closed lactone form of camptothecin helps stabilize the cleavage complex.
Therefore, the present patent provides a method for lactone forms of camptothecin that has a 7
It is recommended that lower pH levels be used. The patent suggests administering the compound with a pharmaceutically acceptable salt.

US Pat. No. 5,447,936 states that agents in HECPT form are more effective at inhibiting topoisomerase-I in acidic environments than in cells with high intracellular pH levels. I do. This patent describes administering the agent with an organic carboxylic acid, such as citric acid.

[0013] US Pat. No. 5,225,404 describes the administration of a camptothecin compound with a water-based solvent for the water-soluble compound, such as normal saline or phosphate buffered saline solution. The patent shows that diarrhea and signs of cystitis were prevented and no overall toxicity was obtained.

US Pat. No. 5,637,770 shows the preparation of hexacyclic compounds obtained by adding a water-soluble ring to camptothecin. It had characteristics superior to camptothecin.
US Patent No. 5,633,016 describes a combination cancer therapy that involves administering an effective amount of topotecan with cisplatin.

US Patent No. 5,633,260 discloses 7-11-substituted camptothecin derivatives. This patent states that keeping the pH of the formulation acidic (3-4) is important in reducing the slow conversion of 11,7-HECPT lactone by E-ring-hydroxylated carboxylate which occurs at physiological pH. Is also described. The patent defines a controlled dose to eliminate the toxicity of the compound.

US Pat. No. 5,652,244 describes a method of treating human carcinoma with a camptothecin derivative. U.S. Patent No. 5,658,920 describes hexacyclic derivative of camptothecin.

US Pat. No. 5,597,829 discloses that CPT is excreted unchanged by the kidneys, but the administered drug cannot make up a large proportion in urine. The patent suggests that enhanced renal excretion of the carboxylate form of CPT occurs when exposed to a pH below 5. Therefore, drug administration to ensure an acidic pH value by administering the compound with an organic carboxylic acid is recommended.

US Pat. No. 5,674,874 describes the pharmacological conversion of CPT11 to HECPT. This patent describes the administration of a compound in an amount sufficient to maintain the pH of the formulation between about 2 and about 6 by administration of a pharmaceutically acceptable acid.

[0019] Cancer Investigation, Volume 14, supplement 1, No. 31 describes the use of irinotecan (CPT11) to treat colon and non-small cell lung cancer.
This publication confirms that the incidence of Grade 4 diarrhea associated with CPT11 administration decreased from 17% to 5% after the indication of aggressive loperimide therapy.

Irinotecan Approved for Advance Colorectal Cancer, Med.Sci. Bull 1996
Volume 18, No. 12, states that diarrhea is a common side effect of irinotecan administration.

[0021] Journal of the National Cancer Institute, September 4, 1996, Vol. 88,
No. 17 suggests that overproduction of sulfomucine in the cecum may be a major cause of CPT-11-induced diarrhea.

[0022] The Camptosar Patient Management Guidelines suggest that administering loperimide and gatrade avoids the diarrheal side effects of Camptosar.

The present invention overcomes diarrhea, one of the major side effects associated with the administration of camptothecin compounds, especially irinotecan hydrochloride. This is one of the major deficiencies in the prior art in delivering irinotecan hydrochloride for treatment of tumors. The present invention overcomes the diarrhea side effects associated with the administration of irinotecan hydrochloride and related compounds.

SUMMARY OF THE INVENTION The present invention provides a method of administering camptothecin, preferably irinotecan hydrochloride and its derivatives, which is cleared by the liver.

The present invention relates to a method for suppressing diarrheal side effects of camptothecin compounds purified by the liver, such as, but not limited to, irinotecan hydrochloride (CPT-11), SN38-Glu and SN-38. And administering irinotecan hydrochloride while maintaining the pH at an alkaline pH.

The present invention provides a camptothecin compound while maintaining the small intestinal lumen at an alkaline pH,
Also provided are methods of treating cancer comprising, for example, administering irinotecan hydrochloride.

In a preferred embodiment, the cancer is selected from, but not limited to, breast cancer, ovarian cancer, colon cancer, malignant melanoma, small cell lung cancer, thyroid cancer, lymphoma and leukemia.

In another embodiment, the present invention provides a method of treating AIDS comprising administering irinotecan hydrochloride while maintaining the small intestinal lumen at an alkaline pH.

The present invention relates to camptothecin compounds, such as irinotecan hydrochloride (CPT-11)
Intravenously, wherein the method comprises the oral administration of bicarbonate and alkaline H ₂ O prior to or simultaneously with the administration of the camptothecin compound.

The present invention relates to camptothecin compounds, such as irinotecan hydrochloride (CPT-11)
, Wherein the composition comprising boric acid is administered orally before or simultaneously with the administration of the camptothecin compound.

The present invention also provides a method of administering a camptothecin compound, comprising orally administering a composition containing ursodeoxycholic acid before or simultaneously with the administration of the camptothecin compound.

Throughout the description of the invention in which the compositions, kits and methods contain or include particular components, the compositions of the invention may consist essentially of, or consist of, the listed components. Is intended by the present inventors.

The above and other objects of the present invention will become apparent to those skilled in the art from the following detailed description and drawings, in which only preferred embodiments of the invention are shown and described solely by the description of the best mode of carrying out the invention. It will be easily apparent. As will be readily appreciated, the invention is capable of modifications within the skill of the relevant art without departing from the spirit and scope of the invention.

Description of the Invention [0034] Knowledge of the cellular transport mechanism of camptothecin compounds, such as CPT-11 and its metabolites, by the small intestine may be found in camptothecin compounds, such as CPT-
11 is a critical step in understanding the mechanisms that induce diarrhea, as well as its large interpatient variability in pharmacokinetics. We have reviewed the uptake of several camptothecin compounds, CPT-11 and SN-38, by small intestinal epithelial cells. The results provide a new plan for an approach to prevent diarrhea and large inter-patient variability in pharmacokinetics in the clinical practice of treating cancer and tumors with irinotecan hydrochloride and its related compounds.

The present invention relates to camptothecin compounds such as irinotecan hydrochloride (CPT-11)
, SN-38-Glu, N-38 and derivatives thereof, which comprises administering irinotecan hydrochloride while maintaining bile and / or small intestinal lumen at an alkaline pH. I do. In a preferred embodiment,
Small intestine lumen is held to alkaline pH by administration of bicarbonate and alkaline H _{2 O.} Bicarbonate levels and alkaline pH are appropriate to reduce uptake of the camptothecin compound, and thus to reduce cytotoxic side effects such as diarrhea. The camptothecin compound or irinotecan hydrochloride can be administered intravenously, orally or intramuscularly. The method of the present invention inhibits reabsorption and reduces lactone uptake of CPT-11 and SN-38 by the small intestine, thus reducing diarrheal side effects associated with camptothecin compounds, such as irinotecan hydrochloride.

The present invention also provides a method for treating cancer comprising administering irinotecan hydrochloride and its derivatives or mixtures thereof while maintaining the small intestinal lumen at an alkaline pH. In a preferred embodiment, the cancer is selected from, but not limited to, the group consisting of breast, ovarian, colon, malignant melanoma, small cell lung, thyroid, lymphoma and leukemia. The alkaline pH can be a pH from about 7 to about 10. In another embodiment, the cancer is 7-hydroxymethylcamptothecin, irinotecan hydrochloride, aminocamptothecin, DX-8951 while maintaining the small intestinal lumen at an alkaline pH.
It is treated by administering a compound selected from F, SN-38, HAR4, HAR5, HAR6, HAR7, HAR8 and topotecan.

The present invention advantageously provides a method of treating AIDS comprising administering irinotecan hydrochloride or a derivative thereof while maintaining the small intestinal lumen at an alkaline pH.

[0038] Pharmaceutical compositions and kits comprising irinotecan hydrochloride are administered in combination with a bicarbonate selected from sodium bicarbonate, magnesium bicarbonate and potassium bicarbonate. Alternatively, irinotecan hydrochloride (CPT-11) can be administered in combination with a composition that includes boric acid. This chemical is used in buffer compositions, for example, in Britton-Robinson buffer and has a strong alkaline buffering action.

The present invention also provides a method of administering a camptothecin compound, comprising orally administering a composition comprising ursodeoxycholic acid before or simultaneously with the administration of the camptothecin compound. The composition is optionally administered with a bicarbonate. Ursodeoxycholic acid stimulates bicarbonate secreted into bile.

The following examples demonstrate the ability to reduce diarrheal side effects of irinotecan hydrochloride compounds according to the methods of the present invention.

EXAMPLES Drugs and Animals ¹⁴ C-labeled SN-38 (3.68 MBg / mg) and ¹⁴ C-labeled C
PT-11 (1.47 MBg / mg) was obtained from Daiichi Pharmaceutical Co., Ltd.
Courtesy of Tokyo, Japan). Unlabeled CPT-11, SN-38
And SN-38-Glu were supplied by Yakult Honsha Co., Ltd. (Tokyo, Japan). ¹⁴ C-labeled SN-38 was dissolved in DMSO at a final concentration of 2 μM because it was very hydrophobic and did not dissolve well in water. DMSO is 2%
It was confirmed that it did not affect the initial uptake of labeled CPT-11 and SN-38. Other drugs were dissolved in distilled water. The lactone and carboxylate forms of ¹⁴ C-labeled CPT-11 and SN-38 were generated by dissolving the compound overnight in 50 mM phosphate buffer at pH 6 or 9, respectively. DNP-SG was made chemically from glutathione and CDNB (1-chloro-2,4-dinitrobenzene). All other reagents were of analytical grade.
Mature male Golden Syrian hamsters (6-8 weeks old) whose model showed a bile acid profile similar to that observed in humans (28) were used.

(Preparation of small intestine cells) Small intestine cells were isolated as described previously (28, 29). In short, a male hamster was treated with sodium pentobarbital (Nembutol 70 mg / 1 kg body weight).
). The entire small intestine was removed. The small intestinal lumen was washed with a 37 ° C. Hank's solution.
The pouches of the ileum (12.5 cm from the cecum) and jejunum (remaining small intestine), as well as the anal (12.5 cm from the cecum) and buccal sites (other small intestinal segments) of the small intestine were washed. The capsules were treated with an oxygenation buffer containing sodium citrate (96 mM NaCl
, 1.5 mM KCl, 5.6 mM KH ₂ PO ₄ , 27 mM sodium citrate, pH 7.3) and incubated in the same buffer at 37 ° C. for 10 minutes. The capsule was then emptied and oxygenated buffer containing EDTA (140 mM N
aCl, 16 mM Na ₂ HPO ₄ , 2 mM EDTA, 0.5 mM dithiothreitol, pH 7.3) and incubated at 37 ° C. for 10 minutes. Each sac was then placed in a Petri dish and gently agitated for 1 minute. The buffer containing small intestine cells is recovered in 50 mL of Hank's solution, washed twice, and 10 ⁶ cells in 1 ml of Hank's medium (cell stock solution containing 0.5% bovine serum albumin, pH 7.4). Was adjusted to the ratio.

[0043] The ⁽¹⁴ C-each determination of cellular uptake of labeled CPT-11 and SN-38) rapid vacuum filtration assay ^(28,29), 14 C- uptake of labeled CPT-11 and SN-38 It was measured. 0.95 ml of the cell suspension was incubated in a 37 ° C. water bath with stirring for 15 minutes. Labeled SN-38 or C at 37 ° C
By addition of 0.05 ml of PBS (at pH 3 or 9) containing PT-11,
The acquisition was started. At various intervals of time, aliquots of 100 μL of sample were placed at 4 ° C.
Diluted in 3 mL of Hank's medium with to stop uptake. The stop solution containing the cells was applied under vacuum (20 psi) to a glass microfiber filter (Glass
(Fibre Filter Circles G4, Fisherbrand, PA). The cells were
Washed once with 5 mL of Hank's medium (4 ° C.) containing 5% bovine serum albumin and once with 20 mL of Hank's solution (4 ° C.). The filtrate is used as a scintillation solution (Ultra Go
(ld, Packard, CT) was placed in a vial containing 4 mL and counted on a beta scintillation counter (LS3801, Beckman, MD).

Three minutes before ¹⁴ C-CPT-11 or ¹⁴ C-SN-38 (2 μM), a metabolic inhibitor 2,4-dinitrophenol (1 mM) was added to examine the effect of the drug. The effect of 20 mM taurocholic acid (TCA) on the uptake of CPT-11 and SN-38 was determined by comparing ¹⁴ C-CPT-11 (20 μM) in Hank's solution at pH 7.4 with and without TCA. ) And ¹⁴ C-SN-38 (2
(μM) after overnight incubation. The effect of 200 μM of DNP-SG or SN-38-Glu was also determined by adding these agents to cell preparations, resulting in 7C of ¹⁴ C-CPT-11 (20 μM) and ¹⁴ C-SN-38 (2 μM).
Checked a minute ago.

The effect of physiological pH on the initial intestinal uptake rates of CPT-11 and SN-38 was determined by ¹⁴ C in phosphate buffers at pH 6.2, 6.8, 7.4 and 8, respectively.
-Investigated after overnight incubation of CPT-11 (20 μM) and ¹⁴ C-SN-38 (2 μM).

Estimation of micelle formation To assess whether CPT-11 and SN-38 form micelles,
The agents were incubated overnight at pH 4 and 9 in calcium and magnesium free Hank's solution containing 10 mM TCA. Each solution was prepared at a constant speed of 0.04 ml / min using a 1000 molecular weight cut membrane YM1 (Diaflo, Amicon
, MA). Once filtration was stopped, the radioactivity in the initial solution and in the filtrate and the retentate after filtration was determined as previously described.

Cytotoxicity Assay A rapid colorimetric assay for mitochondrial dehydrogenase activity was modified to
Used for estimation of cytotoxicity of -38 (Mosmann, 1983). In short, HT
Twenty-nine cells were seeded in 12-well plates (Falcon-3043, Lincoln Park, NJ) and after 48 hours SN-38 was added at pH 6.2, 6.8, 7.4 and 8. After a 24-hour exposure, the cells were washed twice and subjected to a drug-free incubation for 24 hours. The cells were then incubated with 0.5 mg / ml of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl-tetrazolium bromide (MTT) for 4 hours and then incubated in 0.01 N HCl. The blue formazan crystals were solubilized by addition of 10% n-dodecyl sulfate sodium salt (SDS) and incubation overnight. The formation of the blue formazan compound is determined spectrophotometrically at 560 nm (Ultraspec 4050, LKB, Bromma, S
weden).

Statistical Analysis The initial rate of uptake of CPT-11 or SN-38 was obtained from linear regression analysis of each regression line obtained from plots of uptake as a function of time. The initial uptake rate was plotted against the corresponding concentration. Data in the equation _{V = (V m ax S)} / (K m + S) + K d S ( wherein, V is represent uptake initial _{velocity, V max} is the uptake rate maximum, _{K m} is the Michaelis constant apparent , _Kd is the diffusion rate, and S is the concentration of CPT-11 or SN-38), fitted by a least squares non-linear regression analysis (SigmaStat, Jandel Scientific, CA).

The comparison between the two groups was evaluated by the Mann-Whitney rank sum test. Kruskal-Wallis one-way analysis of rank variance for significant differences between more than two groups
A number of comparisons to the control group were performed by the One Way Analysis of Variance on Ranks, followed by Dunn's method. The correlation between the initial rate of SN-38 uptake and cytotoxicity was plotted by a simple least squares regression method.

(CPT-11 and SN-38 lactone and carboxyl
Incorporation of 20 μM in both lactone and carboxylate forms by isolated jejunal cells ¹⁴ C-CPT-11 and 2 μM¹⁴Time-dependent uptake of C-SN-38
Shown in FIG. Extrapolation of the uptake value at time 0 indicates the adsorption of the cell surface to the labeled drug.
This results in a positive interference indicating non-specific binding. Lactone and carboxylate
Each uptake of both forms CPT-11 and SN-38 takes up to 90 seconds
During the period, it was linear. Therefore, the initial acquisition speed is linear for acquisition during the initial period.
Determined by regression fit. Lactone and carboxylate forms of each drug
The comparison of the uptake rate between the carboxylate form and the
It showed faster uptake of both PT-11 and SN-38 lactone (FIG. 2).
).

Table 1 shows that 20 μM ¹⁴ C-CPT-11 and 2 by jejunal and ileal cells.
The initial uptake rate of each of μM of ¹⁴ C-SN-38 is summarized. CPT-11
And SN-38 lactones were taken up faster than their carboxylate forms in cells from both small intestinal regions, but no significant difference was observed between jejunal and ileal cells.

(Transport System of CPT-11 and SN-38 Lactone and Carboxylate) The initial uptake rate of each of CPT-11 lactone and carboxylate was calculated as follows:
Plotted as a function of concentration, the data were plotted for both jejunal and ileal cells using a least squares non-linear regression analysis with the equation v = (V _max S) / (K _m + S) + K _d S (
As adapted more (FIG. 3), the predominant component of CPT-11 lactone uptake is desaturability, suggesting uptake by passive diffusion or fluid phase endocytosis. Analysis of the CPT-11 carboxylate uptake curve also indicated at least two separate components of the uptake process. The saturable components of the curves are the maximum uptake rates (V _max ) of 147 and 157 pmol / 10 cells ⁶ / min / μM, and 51.3 and 50.5 μm in jejunal and ileal cells, respectively.
It is characterized by the Michaelis constant (K _m ) of M. The small desaturable components are <
It was characterized by a diffusion constant of 0.05 pmol / 10 ⁶ cells / min / μM and showed less than one-twelfth the value for CPT-11 lactone in cells in both small intestinal regions (Table 2).
In addition, the Kd for CPT-11 lactone is 1.8- for SN-38 lactone.
It was 2.5 times lower.

Initial uptake rates of SN-38 lactone and carboxylate were plotted as a function of concentration (FIG. 4). The maximum concentration of SN-38 used in this study was below 2 μM due to the low solubility of the compound, thus making it difficult to determine the saturable and unsaturated components of the uptake. In this concentration range, uptake of SN-38 lactone and carboxylate was largely unsaturated (Figure 4).
).

[0054] Carrier-mediated transport is known to be inhibited by metabolic toxins, such as 2,4-dinitrophenol, which interfere with cellular metabolism and reduce the energy production response (23). Thus, 2,4-dinitrophenol was used in applicants' studies to determine the mechanism of incorporation of CPT-11 and SN-38 lactone and carboxylate, respectively. The results of this study are summarized in Table 3. The uptake rate of both CPT-11 and SN-38 lactone was 2,4-
Although not significantly affected by the addition of dinitrophenol, the uptake rates of CPT-11 and SN-38 carboxylate were reduced by 2,4-dinitrophenol to 22.6 and 30.8%, respectively, which were Suggest an active transport mechanism for both compounds.

2,4-Dinitrophenol-S-glutathione (DNP-SG) is known to be a substrate for an active multispecific organic anion transporter (cMOAT) in the liver (24). ). In addition, the binding of SN-38 by UDP-glucuronyltransferase indicates that SN-38-, a substrate for liver cMOAT, is also present.
This leads to the formation of Glu (12, 17). To determine whether CPT-11 carboxylate and / or SN-38 carboxylate are transported in small intestinal cells via a cMOAT-like mechanism, DNP-SG and SN-38-G
The rate of uptake of CPT-11 and SN-38 was determined in the presence or absence of lu. The results are summarized in Table 3. DNP-SG and SN-38-Glu
Uptake of the carboxylate form of SN-38 was significantly inhibited by over 60%, while uptake of CPT-11 carboxylate remained unchanged. The rate of uptake of the lactone forms of CPT-11 and SN-38 was not significantly affected by the presence of DNP-SG or SN-38-Glu.

Concentration of Taurocholic Acid (TCA) above the Critical Micellar Concentration on Both Micelles Formation and Initial Uptake Rate of CPT-11 and SN-38 Compared to Both CPT-11 and SN-38 To form micelles that cannot pass through the 1,000 molecular weight cut membrane (25). This property was used to determine whether CPT-11 and SN-38 lactone and carboxylate could associate with TCA micelles. The results reported in FIG. 5 show that TCA significantly reduced the% monomer concentration of CPT-11 lactone and carboxylate, and SN-38 lactone.
However, SN-38 carboxylate did not significantly associate with TCA micelles.

Next, Applicants examined the effect of micelle formation on cell uptake of CPT-11 and SN-38. In this series of experiments, cells from the jejunum and ileum were merged. In the presence of 20 mM TCA, the initial uptake rates of CPT-11 and SN-38 (mean ± SD) were respectively 48.5 ± 10.
8 and 69.3 ± 12.7% (n = 5, p = 0.015 and p = 15 for Mann-Whitney test, CPT-11 and SN-38, respectively)
0.343).

Effect of pH and Bicarbonate on Initial Uptake Rate of CPT-11 and SN-38 Interconversion between lactone and carboxylate CPT-11 and SN-38, respectively, is reversible and pH driven. (11). 20 μM of ¹⁴ C-CPT-
Physiological pH (p) affects the initial uptake rate of 11 and 2 μM ¹⁴ C-SN-38.
H6.2 to 8) were examined. The results summarized in FIG. 6 show that CPT-11 and SPT
9 shows that the uptake rate of N-38 was significantly reduced by about 65% at pH above 6.8. Changes in uptake were also observed when measuring the initial uptake rates of CPT-11 and SN-38 in the presence and absence of bicarbonate. Incorporation of CPT-11 and SN-38 was reduced when the HEPES component of the Hank buffer was replaced with sodium bicarbonate and the pH was adjusted above 7.

Using hamster small intestine cells, the results of this study indicate that both non-ionic lactone forms of CPT-11 and SN-38 are primarily due to a passive mechanism.
However, each was absorbed at several times the rate of their anionic carboxylate form (Tables 1, 2 and 3; Figures 2, 3 and 4). Significance was found in the transport mechanism between jejunal and ileal cells, as well as in motility parameters (Tables 2 and 3). Although not shown, CPT-11 was used with both cecal and colon cells.
Similar results were observed when the uptake of SN-38 and SN-38 was performed (26
).

[0060] The isolated hamster small intestine cells have a limited viability to
It is not the best model to estimate the cytotoxic effects of N-38 (
Gore et al., 1993). Therefore, HT29 cells have 2 μM [ ¹⁴ C] SN.
It was also used to examine the relative effect of physiological pH on both the initial uptake rate of -38 and the cytotoxicity of SN-38 at 0.4 μM. The initial uptake rate of SN-38 was lower in HT-29 cells than in isolated hamster small intestine cells (Figures 3 and 4). However, similar to that observed in isolated hamster small intestine cells, HT
The uptake rate of SN-38 in 29 cells at pH 6.2 and 6.8
Significantly higher than H7.4 and 8.0 (Kruskal-Wallis test: p =
0.008, Dunn's method: p <0.05) (FIG. 7). SN- against HT-29 cells
The cytotoxicity of 38 was significantly higher at pH 6.2 and 6.8 than at pH 7.4 and 8.0 (Kruskal-Wallis test: p = 0.007, Dunn's method: p <
0.05). FIG. 5 shows the relationship between the initial rate of [ ¹⁴ C] SN-38 uptake and the cytotoxicity of SN-38, which shows that with decreasing pH, high uptake rates It shows that it was correlated with the action.

The results clearly show that CPT-11 and S
It was shown that N-38 carboxylate was incorporated (Tables 2 and 3,
(Fig. 3). Recently, cMOAT, which is mainly expressed in the hepatic canalicular membrane, has been proposed to transport some types of organic anions into bile as the primary active transport system (2).
4, 27-29). In addition, hepatic cMOAT has been reported to be involved in the bile excretion of the anions SN-38 carboxylate, SN-38-Glu lactone and carboxylate (12, 17). The anion CPT-11 carboxylate was reported to be only partially eliminated by cMOAT (1
2, 17). The inventor's work has shown that SPT, as opposed to CPT-11 carboxylate,
The initial uptake rate of N-38 carboxylate is DNP-SG and SN-38-G
This indicates that lu was significantly suppressed (Table 3). These results are consistent with those of Cho et al. (12, 17) using liver tubule membrane vesicles. Therefore, this study demonstrates that cMOAT or cMOAT in the jejunal and ileal cell uptake of SN-38.
Support the involvement of transporters.

The present invention relates to CPT-11 lactone and carboxylate, and SN-3
We also report that 8 lactones can form micelles in the presence of high concentrations of TCA (FIG. 5). The percentage of monomer concentration ranged from 38 to 47%. These concentrations differ from those of long chain fatty acids (ie, 2.3% for oleic acid) and cholesterol (3%). Furthermore, micelle formation suppressed CPT-11 uptake, which differs from the positive role played by bile acid micelle formation in intestinal uptake of long chain fatty acids and cholesterol. These results support data indicating that micelle formation suppressed uptake of short chain fatty acids, such as palmitic acid.

As described in FIG. 1, the conversion of CPT-11 and SN-38 lactone to carboxylate is pH driven (11, 12). At pH 7.4, SN-
It has previously been reported that 13% of each of 38 and CPT-11 were in lactone form (30). This study demonstrated that the initial uptake rates of CPT-11 and SN-38 were neutral or alkaline pH (pH 7) at acidic pH (pH 6.2 and 6.8).
. 4 and 8) (FIG. 6). 1) At acidic pH, the non-ionic lactone forms CPT-11 and SN-38 are passively transported, and 2) at neutral / basic pH, the anionic carboxylate form of CPT-11.
And SN-38 are mainly actively absorbed, and 3) CPT-11 and SN
Given the fact that the uptake rate of -38 lactones is several times faster than their carboxylate forms, the mechanism of uptake of CPT-11 and SN-38 by small intestinal cells is very similar to that of short chain fatty acids. This hypothesis states that, as with short chain fatty acids, micelle formation reduces uptake of CPT-11 and SN-38,
It appears that the uptake of PT-11 and SN-38 is not restricted to the small intestine but is also supported by the fact that it also occurs in the cecum and colon.

Thus, as with short chain fatty acids, alkalinization of bile and luminal contents reduces small intestinal uptake of CPT-11 and SN-38. The bile content of CPT-11 and its metabolites was determined for two men treated with cisplatin and intravenously administered CPT-11 (9). The main component of bile is CPT-11 (75
. 6-91.9%), while SN-38 and SN-38-Glu were minor constituents, 0.9-3.3% and 7.3-18.9%, respectively. In addition, the pH of human bile has been reported to be in the range of 6.5 to 8.0 (31).
). Thus, not only the carboxylate form but also the lactone form of CPT-11 is not only pharmacokinetic, since CPT-11 lactone is absorbed more by small intestinal epithelial cells and CPT-11 levels in the enterohepatic circulation are increased. It is thought to play an important role.

SN-38 is mainly active as a lactone form, while SN-38 carboxylate shows only small topoisomerase I-inhibitory activity (32). 24 hours after IV injection of ¹⁴ C-SN-38 using rat whole body autoradiography,
Radioactivity was found exclusively in the gastrointestinal tract (33). SN-38 shows strong cytotoxicity, SN-38-Glu is an inactivated glucuronidated form of SN-38, and CPT-11 is much less cytotoxic than SN-38 ( Kawato et al
., 1991). The accumulation of SN-38 in the small intestine has been shown in rats (Atsumi et al., 19
95) In nude mice, it was thought to be involved in diarrhea due to CPT-11 administration (Araki et al., 1993). Disruption of small intestinal epithelium in the cecum was observed in mice and rats that developed diarrhea after CPT-11 administration (Takatsuna et al., 1996).
Ikuno et al., 1995; Araki et al., 1993). Diarrhea induced by CPT-11 administration in humans has been reported to be secretory diarrhea (Bleiberg and Cvitk).
ovic, 1996). However, in patients, we observed lethal small intestinal damage associated with CPT-11-induced side effects, as reported in animal models (Kobayashi et al., 1998b).

Furthermore, the accumulation of SN-38, ie the radioactivity, was exclusively found in the gastrointestinal tract (33
). The accumulation of SN-38 in the small intestine has been shown to be involved in diarrhea due to CPT-11 in nude mice (34). Disruption of the small intestinal epithelium in the cecum was thought to be involved in CPT-11-induced diarrhea in rats (35). Finally, clinical estimates in Europe have reported that diarrhea induced by CPT-11 is secretory diarrhea (36), whereas in our study applicants reported that the incidence of severe small intestinal injury was reduced. I saw (37).

Dissection showed the presence of pseudomembrane jejuno-ileitis, which under the light microscope is characterized by disruption of the small intestinal epithelium, suggesting that damaging diarrhea can occur in severe cases. The mechanism for CPT-11-induced diarrhea is that the intestinal epithelium mainly reabsorbs lactone SN-38 and CPT-11,
High exposure of the small intestinal epithelium to these metabolites is thought to cause structural and functional damage to the small intestinal tract.

As suggested in this study, alkalization of bile and / or small intestinal luminal contents reduces uptake and exposure of small intestinal epithelium to CPT-11 and SN-38 lactone. The absorption of short chain fatty acids in the small intestine has been studied for the past decade, but conflicting results have been reported. As shown in FIG. 6, it is believed that pH reduction induces increased uptake of short chain fatty acids. Therefore, camptothecin and CP
The treatment of the present invention for T-11-induced diarrhea is for two purposes: 1) alkalinization of the small intestinal lumen, and 2) purification of CPT-11 and SN-38 from the body (ie, defecation control). concentrate. Prior to and / or simultaneously with the standard TV administration of CPT-11, a combination of sodium bicarbonate, magnesium oxide and water at a pH greater than 7 is orally administered to the patient. The incidence of diarrhea is reduced.

The relationship between SN-38 cellular uptake and its associated cytotoxicity was also estimated in studies of the present invention. It was found that cell uptake and cytotoxicity of SN-38 in HT29 cells were pH-dependent, and that cytotoxicity correlated well with the initial uptake rate (FIG. 8). As noted above, at acidic pH, the predominant form of SN-38 is believed to be lactone. This results in both higher cellular uptake and intracellular concentrations of SN-38 lactone. SN-38 is mainly active in the lactone form, while SN-38
38 carboxylate shows only small topoisomerase T inhibitory activity (Kawato et al.
al., 1991), so this may be related to increased cell death. Therefore,
One possible mechanism for CPT-11-induced diarrhea may involve reabsorption of SN-38 lactone by the small intestinal epithelium and resulting structural and functional damage to the small intestinal tract.

In summary, the study of the present invention demonstrates that CPT-11 and SN-3 by intestinal epithelial cells
This is the first estimate of the uptake of 8. Both CPT-11 and SN-38 lactone are passively transported, while both CPT-11 and SN-38 carboxylate are actively absorbed. The uptake rates of CPT-11 and SN-38 lactones are several times higher than for the respective carboxylate forms. In addition, high uptake rates of SN-38 are associated with increased cytotoxic effects in HT29 cells. These findings indicate that the conversion to carboxylate is significant for CPT-11 and SN.
Suggests that both -38 reduce cellular uptake. Thus, these findings provide support for alkalization of the small intestinal lumen as one possible mechanism for reducing reabsorption of CPT-11 and SN-38 in clinical practice. Limiting small intestinal reabsorption can modulate the bioavailability of the drug, which in turn circulates in the enterohepatic circulation, to reduce the toxic side effects of SN-38 on small intestinal epithelium.

The result is a camptothecin compound that is cleared in clinical practice and by the liver
For example, it has a strong direct effect on the administration of irinotecan hydrochloride and its derivatives.
The present inventors have discovered that camptothecin compounds that are cleared by the liver, such as CPT-11
Provides oral alkalinization by administration of

Finally, the present inventors have discovered that camptothecin compounds such as CPT-11 by the small intestine
And the acquisition of SN-38 will be described. Both CPT-11 and SN-38 lactones are passively transported by small intestinal cells. CPT-11 and SN-38
Both carboxylates are actively absorbed, but by different transport mechanisms. The formation of micelles by TCA reduced the uptake of both CPT-11 and SN-38. The rate of uptake of CPT-11 and SN-38 lactones is several times that of the carboxylate form, while the rate of uptake in the presence of bicarbonate is
And it decreased under pH increasing conditions. These findings regarding CPT-11 and SN-38 may be useful in clinical practice.

Initial rate of uptake of CPT-11 and SN-38 by the small intestine

[Table 1] [ ¹⁴ C] CPT-11 (20 μM) and [ ¹⁴ C] SN-38 (2 μM)
Of lactone and carboxylate were compared. Results are expressed as pmol / 10 ⁶ cells / min and are the mean ± SE of 10 experiments. Mann-Whitney test was used for statistical analysis.

Motor parameters of CPT-11 and SN-38 uptake by the small intestine

[Table 2] ( ^* ): Due to limited solubility, only SN-38 concentrations up to 2 μM were examined. ( ⁺ ): Since SN-38 carboxylate is determined to be actively transported in the presence of dinitrophenol from estimates of its uptake (Table 3), these values are considered to be physiologically relevant. I can't. Note: The data were fit equation _{V = (V max · S)} / (K m + S) + K d · S least squares non-linear regression analysis using (SigmaStat, Jandel Scientific, CA) by. V _max (pmol / 10 ⁶ cells / min) is the maximum uptake rate and K _m (μ
M) is the apparent Michaelis constant, K _d (pmol / 10 ⁶ cells / min / μ
M) is the diffusion rate and S (μM) is the concentration of CPT-11 or SN-38. Values are means ± SE. CPT-11 lactone, SN-38 major constituent of lactones and SN-38 carboxylate uptake, respectively, are non-saturable, therefore, _{K m} and _{V max} values were not determined (ND).

Effect of dinitrophenol on the initial uptake rate of CPT-11 and SN-38,
Effect of SN-38-Glu and DNP-SG

[Table 3]NE Not estimated; not significantly different from NS control. Note: dinitrophenol, SN-38 glucuronide (SN38-Glu) or
2,4-Dinitrophenyl-S-glutathione (DNP-SG) was each [ ¹⁴ C] CPT-11 (20 μM) and [¹⁴C] With SN-38 (2 μM)
Prior to addition, they were added to the indicator cell suspension (see Materials and Methods for details).
The initial uptake rate of CPT-11 and SN-38 in the presence of each compound was
It was expressed as a percentage (%). Between dinitrophenol and its control
The difference is¹It was evaluated by the Mann-Whitney test. SN-38-Glu, DNP
-The difference between SG and their controls is²Assessed by the Kruskal-Wallis test
, The significant difference from each control was analyzed by the Dan method (^*p <0.05).

Irinotecan Hydrochloride Formulation In a preferred embodiment, at a pH greater than about 7, provided to a patient treated with a camptothecin compound, eg, CPT-11 and its derivatives, preferably from 8 to 1
Administer sodium bicarbonate, magnesium oxide and water at a pH of 0, most preferably at a pH of 8-9.

In addition, the CPT-11 compounds of the invention may be administered in unit dosage forms containing an appropriate amount of the active ingredient, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile parenteral External solutions or suspensions, oral solutions or suspensions, oil-in-water or water-in-oil emulsions, etc. are useful in pharmaceutical compositions for systemic administration to humans and animals. For oral administration, solid or fluid unit dosage forms can be prepared using the compounds. The compounds are useful in pharmaceutical compositions (% by weight) of the active ingredient with carriers or vehicles in the composition at about 1-20%, preferably about 5-15%.

Fluid or solid unit dosage forms can be readily prepared for oral administration. For example, CPT-11 is functionally compatible with conventional ingredients such as dicalcium phosphate, aluminum magnesium silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methylcellulose and pharmaceutical excipients or carriers. Can be mixed with similar materials. A depot formulation may optionally be used. Capsules can be formulated by mixing the compound with an inert formulation diluent and inserting the mixture into a suitably sized hard gelatin capsule. If soft capsules are desired, the compound slurry can be machine encapsulated in a gelatin capsule with an acceptable vegetable, light or other inert oil.

Suspensions, syrups and elixirs can be used for oral administration in fluid unit dosage form. Fluid formulations, including oils, may be used for oil-soluble forms. Vegetable oils, such as corn oil, peanut oil or safflower oil, produce an acceptable fluid formulation with, for example, flavoring agents, sweetening agents and any preservatives. Surfactants can be added to the water to produce a syrup for fluid unit dosage. Water-alcoholic agents having an acceptable sweetening agent, for example, sugar, saccharin or biological sweetening agents and flavoring agents in elixir form may also be used.

Formulations for parenteral and suppository administration may also be obtained using techniques standard in the art.

Suitable pharmaceutical carriers include sterile water, saline, dextrose, dextrose in water or saline, condensate of castor oil and ethylene oxide, combining about 30 to about 35 moles of ethylene oxide per mole of castor oil, Liquid acids, lower alkanols, oils such as corn oil, peanut oil, sesame oil and the like, with emulsifiers such as fatty acid mono- or di-glycerides or phosphatides such as lecithin;
Glycol; polyalkyl glycol; aqueous medium in the presence of a suspending agent, such as sodium carboxymethylcellulose; sodium alginate; poly (vinylpyrrolidone), etc. alone or with a suitable dispersing agent such as lecithin; polyoxyethylene stearate. And the like. The carrier may also contain adjuvants such as preserving, stabilizing, wetting, emulsifying, and the like, along with the penetration enhancers of the present invention.

The effective dosage for a mammal can vary depending on factors such as the age, weight, activity level, or condition of the subject being treated. Typically, an effective dose of a compound of the present invention will be about 10 to 10 when administered orally or rectally 1 to 3 times daily.
a ^{mg / m 2 ~700mg / m 2} . CPT-11 is preferably administered once a week,
It can be administered for 1-5 weeks. The frequency and dosage of CPT-11 for cancer and primary treatment is known.

(Administration of Irinotecan Hydrochloride) The average terminal elimination half-life of irinotecan hydrochloride (Pharmacia-Upjohn) is about 6 hours.

The camptothecin compound may be administered alone or in combination with a chemotherapeutic regimen, such as leucovorin, cisplatin, 5-FU, oxyplatin, and other known chemotherapeutic agents. In an alternative embodiment, a camptothecin compound,
For example, irinotecan hydrochloride can be administered with loperamide.

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n derivative irinotecan hydrochloride. Cancer Research, 56, 3752-3757 (1
996).

[Brief description of the drawings]

FIG. 1. CPT-11, SN-38 and SN-38-glucuronide (SN-38-G
lu) shows the structure. The lactone forms of CPT-11 and SN-38 are charged non-ionic and the carboxylate forms of CPT-11 and SN-3
8 is an anion. The lactone form as well as the carboxylate form SN-38-Glu, which carries an additional carboxyl moiety in its glucuronide moiety, is an anion. The reversible conversion between the lactone and carboxylate forms depends on the pH
Drivability.

FIGS. 2A and 2B show the time course of CPT-11 and SN-38 uptake by isolated small intestinal cells. Lactone and carboxylate forms respectively by isolation intestinal cells from the duodenum ^{[14 C] CPT-11 (} 20μM) and ^[14 C
] SN-38 (2 μM) uptake was measured as a function of time. At 0 hours, each drug was added to the small intestine cell suspension maintained at 37 ° C. under permanent shaking. At 15, 30, 45, 60, 90, 120, 240 and 480 seconds, aliquots of the cell suspension were removed and processed as described in Materials and Methods. The results shown are the mean ± SE of n experiments.

FIGS. 3A, 3B, 3C and 3D show the relationship between the initial rate of CPT-11 uptake and its concentration. The initial uptake rate was determined from the linear gradient of cell uptake during the initial 90 second incubation period. The data is expressed by the equation v = (V _max S) / (K _m + S) + K _d S, where V represents the initial capture speed, V _max is the maximum capture speed, and K _m is the apparent Michaelis constant. Where K _d is the diffusion rate and S
Is the concentration of CPT-11) by least squares non-linear regression analysis.

FIGS. 4A and 4B show the relationship between the initial rate of SN-38 uptake and its concentration. Initial uptake rates were determined as described in the legend of FIG. 3 and in the Materials and Methods section. Data were fitted by least squares linear regression. Due to the limited solubility, only concentrations of SN-38 up to 2 μM were tested.

FIG. 5 shows the effect of taurocholate (CPT-11 and SN-38 micelle formation, respectively)
TCA). [ ¹⁴ C] CPT-11 (20 μM) and [ ¹⁴ C]
SN-38 (2 μM) was stored overnight in Hank's solution in the presence or absence of TCA (20 mM). The monomers were separated from the micellic aggregates by ultrafiltration through a 1000 molecular weight cut membrane (YM1) as described in Materials and Methods.
The value is the value of the indicator metabolite in monomeric form, expressed as a percentage of the concentration of the initial solution before ultrafiltration. Comparisons between TCA and controls were estimated by the Mann-Whitney test (). SN-38 carboxylate was significantly different from the other drugs tested in the presence of TCA (Kruskal-Wallis test: p
= 0.023, Student-Newman-Keuls method, p <0.05). Abbreviations used: CPT lactone (CPT lact.), CPT carboxylate (CPT carb.), SN-38 lactone (SN lact.) And SN
-38 carboxylate (SN carb.).

FIGS. 6A and 6B show the effect of pH on the initial rate of CPT-11 and SN-38 uptake. [ ¹⁴ C] CPT-11 (20 μM) and [ ¹⁴ C] S
N-38 (2 μM) was dissolved in PBS at pH 6.2, 6.8, 7.4 and 8.0 and stored overnight. An uptake test was performed by adding the drug to Hank's solution containing small intestinal cells from the whole small intestine. Cruzcal-Wallis test (CPT-
P <0.001 and p <0.001 for 11 and SN-38, respectively.
And the Student-Newman-Keuls method (p <0.05)
The difference in initial uptake rate with pH was analyzed.

FIG. 7 shows the effect of pH on the initial uptake rate of HT29 cells. [ ¹⁴ C] SN-3
8 (2 μM) was dissolved in PBS overnight at pH 6.2, 6.8, 7.4 and 8.0. The uptake test was started by adding this compound to Hank's solution containing HT29 cells. The comparative initial rate of uptake as a function of pH was analyzed by the Kruskal-Wallis test (p <0.001) and the Dunn's method ( ^* p <0.05).

FIG. 8 shows the relationship between initial uptake rate of SN-38 and cytotoxicity. Using HT29 cells, the effect of physiological pH on the initial uptake rate of 2 μM [ ¹⁴ C] SN-38 was estimated as described in the legend to FIG. According to the above MTT test, HT-2
Nine cells were tested for 0.4 μM SN-38 induced cytotoxicity. SN-3
The relationship between the initial uptake rate of No. 8 and cytotoxicity was plotted by a simple least squares regression method.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) // C07D 491/22 C07D 491/22 (A61K 31/4745 (A61K 31/4745 33:10) 33:10 ) (A61K 31/4745 (A61K 31/4745 33:22) 33:22) (A61K 31/4745 (A61K 31/4745 31: 575) 31: 575) (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, M), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, G E, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU , ZA, ZW (72) Inventor Kunihiko Kobayashi 20852 Rockland, Maryland USA # 10401 Building 3 Grosvenor Place 1017 F-term (reference) 4C050 AA01 BB04 CC07 DD08 EE02 FF02 GG03 HH01 4C086 AA01 AA02 CB22 DA11 MA01 MA02 MA05 MA07 MA52 MA66 NA06 ZB26

Claims (17)

[Claims] 1. A method for suppressing diarrheal side effects of a camptothecin compound, comprising:
A method comprising administering the camptothecin compound at an alkaline pH. 2. The camptothecin compound is irinotecan hydrochloride (CPT-
11) The method according to claim 1, wherein the method is selected from the group consisting of SN38-Glu, SN-38 and derivatives thereof. 3. The method of claim 1, wherein said small intestinal lumen and bile are maintained at an alkaline pH. 4. The method of claim 1, wherein said irinotecan hydrochloride is administered intravenously, orally or intramuscularly. 5. The method of claim 1, wherein re-absorption of said camptothecin compound by said small intestine is suppressed. 6. A method for treating cancer comprising administering irinotecan hydrochloride and a derivative thereof while maintaining the small intestinal lumen at an alkaline pH. 7. The method according to claim 6, wherein said cancer is selected from the group consisting of breast cancer, ovarian cancer, colon cancer, malignant melanoma, small cell lung cancer, thyroid cancer, lymphoma and leukemia. 8. The method according to claim 6, wherein said alkaline pH is a pH of 7-10. 9. The method of claim 6, wherein said alkaline pH is from pH 7. 10. The method of claim 6, wherein said alkaline pH is from pH 8. 10. The method of claim 5, wherein said alkaline pH is from pH 9. 11. The method of claim 5, wherein said alkaline pH is from pH 10. 12. A method for treating AIDS, comprising administering irinotecan hydrochloride and a derivative thereof while maintaining the small intestinal lumen at an alkaline pH. 13. The method according to claim 13, wherein the lumen of the small intestine is maintained at an alkaline pH while 7-hydroxy-methylcamptothecin, irinotecan hydrochloride, aminocamptothecin,
DX-8951F, SN-38, HAR4, HAR5, HAR6, HAR7, H
A method for treating cancer, comprising administering a compound selected from the group consisting of AR8 and topotecan. 14. A kit comprising a pharmaceutical composition comprising irinotecan hydrochloride in combination with an amount of bicarbonate suitable for keeping the small intestinal lumen alkaline. 15. The composition according to claim 14, wherein said bicarbonate is selected from the group consisting of sodium bicarbonate, magnesium bicarbonate, potassium bicarbonate and mixtures thereof. 16. A method for administering a camptothecin compound, comprising orally administering a composition containing boric acid before or simultaneously with the administration of the camptothecin compound. 17. A method for administering a camptothecin compound, which comprises orally administering a composition containing ursodeoxycholic acid before or simultaneously with the administration of the camptothecin compound.