Topoisomerase I
Topoisomerase I (Topo I) [2]

In vitro activity: Irinotecan is a topoisomerase I inhibitor. Irinotecan inhibits the growth of HT-29 and LoVo cells, causing comparable amounts of cleavable complexes in both cells, with IC50s of 5.17 ± 1.4 μM and 15.8 ± 5.1 μM, respectively[2]. With an inhibitory concentration (IC50) of 1.3 microM, irinotecan inhibits the growth of human umbilical vein endothelial cells (HUVEC)[3].

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Treatment with Irinotecan (CPT-11) exhibited cytotoxic effects on two human colorectal tumor cell lines (HT29 and SW620). The IC50 values for HT29 and SW620 cells were 0.65 μM and 0.82 μM, respectively. The cytotoxicity was associated with increased formation of DNA single-strand breaks and induction of apoptosis [2]
- Irinotecan (CPT-11) induced apoptosis in murine peritoneal resident macrophages (PRMs) in a dose-dependent manner. At concentrations of 10 μM, 25 μM, and 50 μM, the apoptotic rates of PRMs were 18.3%, 35.7%, and 62.1%, respectively. Western blot analysis showed upregulation of cleaved caspase-3, cleaved caspase-9, and Bax, and downregulation of Bcl-2 [5]

Irinotecan (CPT-11, 5 mg/kg) significantly slows the growth of tumors when injected intratumorally into rats for five days straight over the course of two weeks. In mice, the same effect is achieved by continuously infusing osmotic minipump fluid intraperitoneally. But Irinotecan (10 mg/kg) has no effect on the tumor's ability to grow intraperitoneally[1]. In athymic female mice, irinotecan (CPT-11, 100-300 mg/kg, i.p.) appears to inhibit the growth of HT-29 xenograft tumors by day 21. At doses of 250 and 300 mg/kg, respectively, both the Irinotecan plus TSP-1 (10 mg/kg per day) and the Irinotecan (150 mg/kg) in combination with TSP-1 (20 mg/kg per day) groups are more effective than Irinotecan alone and inhibit tumor growth 84% and 89%, respectively[3].

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Irinotecan (CPT-11) was administered intraperitoneally to mice bearing experimental malignant neuroectodermal tumors at a dose of 100 mg/kg once a week for 3 weeks. It significantly inhibited tumor growth, with a tumor volume reduction rate of 58.6% compared to the control group. No obvious systemic toxicity was observed during the treatment period [1]
- Combination treatment of thrombospondin-1 (TSP-1) and Irinotecan (CPT-11) was tested in mice bearing advanced human colon tumor xenografts. Irinotecan (CPT-11) was given intravenously at 60 mg/kg every 4 days for 3 cycles, and TSP-1 was administered subcutaneously at 2 μg/mouse every other day. The combination therapy resulted in a 72.3% inhibition of tumor growth, which was significantly higher than the 41.5% inhibition by Irinotecan (CPT-11) alone [3]

Topoisomerase I activity assay was performed using purified human Topo I and supercoiled plasmid DNA. The reaction mixture contained different concentrations of Irinotecan (CPT-11), Topo I, and plasmid DNA, and was incubated at 37°C for 30 minutes. The reaction was terminated by adding SDS, and the DNA products were separated by agarose gel electrophoresis. The inhibitory effect of Irinotecan (CPT-11) on Topo I was evaluated by the reduction of relaxed DNA bands [2]

In 20 cm 2 dishes, exponentially growing cells are seeded with the ideal number of cells for each cell line (20,000 for LoVo cells, 100,000 for HT-29 cells). They receive treatment with irinotecan or SN-38 at increasing concentrations for a single cell doubling period (24 hours for LoVo cells and 40 hours for HT-29 cells) after two days. Following a 0.15 M NaCl wash, the cells are cultured in normal medium for two more doubling times before being separated from the support using trypsin-EDTA and counted using a hemocytometer. Subsequently, the drug concentrations that cause a 50% inhibition of growth in cells treated with the drug are estimated as the IC50 values[2].

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For colorectal tumor cell cytotoxicity assay: HT29 and SW620 cells were seeded in 96-well plates at a density of 5×10³ cells/well and incubated overnight. Cells were treated with serial concentrations of Irinotecan (CPT-11) (0.1-10 μM) for 72 hours. Cell viability was measured using a colorimetric assay based on mitochondrial dehydrogenase activity. DNA single-strand breaks were detected by alkaline comet assay, and apoptosis was assessed by flow cytometry after Annexin V-FITC/PI staining [2]
- For peritoneal resident macrophage apoptosis assay: Murine PRMs were isolated and cultured in 6-well plates at 2×10⁵ cells/well. Cells were treated with Irinotecan (CPT-11) at concentrations of 10 μM, 25 μM, and 50 μM for 24 hours. Apoptotic cells were identified by Hoechst 33342 staining and flow cytometry. Western blot analysis was conducted to detect the expression levels of caspase-3, caspase-9, Bax, and Bcl-2 proteins [5]

One cycle of therapy consists of injecting 0.1 cc of the suitable solution intraperitoneally (IV) with irinotecan at a dose of 5 mg/kg per day for 5 days on two consecutive weeks, separated by a 7-day rest period. Over the course of eight weeks, rats receive three cycles. By intratumoral injection, control animals are given 0.1 cc of sterile 0.9% sodium chloride solution according to the same protocol as group II animals[1].

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Malignant neuroectodermal tumor model: Mice were inoculated subcutaneously with tumor cells (1×10⁶ cells/mouse) to establish xenografts. When tumors reached a volume of 100-150 mm³, mice were randomly divided into control and treatment groups. Irinotecan (CPT-11) was dissolved in normal saline and administered intraperitoneally at 100 mg/kg once a week for 3 consecutive weeks. Tumor volume was measured every 3 days using a caliper, and body weight was recorded to monitor toxicity [1]
- Human colon tumor xenograft model: Nude mice were implanted subcutaneously with human colon tumor cells (2×10⁶ cells/mouse). When tumors grew to 200-250 mm³, mice were assigned to three groups: control, Irinotecan (CPT-11) alone, and Irinotecan (CPT-11) + TSP-1. Irinotecan (CPT-11) was dissolved in 5% dextrose solution and administered intravenously at 60 mg/kg every 4 days for 3 cycles. TSP-1 was dissolved in phosphate-buffered saline and injected subcutaneously at 2 μg/mouse every other day. Tumor size and body weight were measured twice a week [3]

Absorption, Distribution and Excretion
When patients with solid tumors received a dose of 125 mg/m², the maximum plasma concentration (Cmax) was 1660 ng/mL. The AUC (0-24) was 10,200 ng·h/mL. When patients with solid tumors received a dose of 340 mg/m², the Cmax was 3392 ng/mL. The AUC (0-24) was 20,604 ng·h/mL. In both patients, the cumulative bile and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) within 48 hours after administration was approximately 25% (100 mg/m²) to 50% (300 mg/m²). The volume of distribution in the terminal elimination phase was 110 L/m² when patients with solid tumors received a dose of 125 mg/m². When administered to patients with solid tumors at a dose of 340 mg/m², the volume of distribution of the terminal elimination phase was 234 L/m².
13.3 L/h/m² [dose 125 mg/m², solid tumor patients]
13.9 L/h/m² [dose 340 mg/m², solid tumor patients]
In two pediatric solid tumor trials, pharmacokinetic parameters of irinotecan and SN-38 were determined at dose levels of 50 mg/m² (60-minute infusion, n=48) and 125 mg/m² (90-minute infusion, n=6), respectively. The clearance (mean ± standard deviation) of irinotecan was 17.3 ± 6.7 L/h/m² at the 50 mg/m² dose group and 16.2 ± 4.6 L/h/m² at the 125 mg/m² dose group, comparable to that in adults. The dose-standardized AUC values for SN-38 were comparable between adults and children. In children receiving a daily dosing regimen (once daily for 5 weeks every 3 weeks; or once daily for 5 weeks every 3 weeks for 2 weeks), the accumulation of irinotecan and SN-38 was extremely low. The clinical pharmacokinetics of irinotecan (CPT11) can be described using a two- or three-compartment model, with a mean terminal half-life of 12 hours, a steady-state volume of distribution of 168 L/m², and a systemic clearance of 15 L/m²/hr. Irinotecan binds to plasma proteins at a rate of 65%. The area under the plasma concentration-time curve (AUC) of both irinotecan and its active metabolite SN38 increases proportionally with the administered dose, but varies considerably among patients. …The mean 24-hour urinary excretion of irinotecan is 17-25% of the administered dose, while the recovery rates of SN38 and its glucuronide in urine are extremely low (0.5% and 6%, respectively). The pharmacokinetics of irinotecan and SN38 are not affected by prior exposure to the parent drug. The AUC of irinotecan and SN38 is significantly associated with leukopenia and sometimes with the severity of diarrhea. Elevated bilirubin levels appear to affect the systemic clearance of irinotecan. Metabolism/Metabolites: Hepatic. The metabolism of irinotecan to the active metabolite SN-38 is primarily mediated by carboxylesterases and occurs mainly in the liver. SN-38 is then primarily bound via UDP-glucuronyltransferase 1A1 (UGT1A1) to form the glucuronide metabolite. …The concentration of SN-38 in the human body is approximately 100 times lower than the corresponding irinotecan concentration, but these concentrations are crucial because SN-38 is 100 to 1000 times more cytotoxic than the parent compound. SN-38 binds to plasma proteins at a rate of 95%. Plasma attenuation of SN-38 is closely related to the attenuation of the parent compound. Irinotecan is extensively metabolized in the liver. The dipiperidine carbonyl group of irinotecan is first removed by a carboxylesterase, yielding the corresponding carboxylic acid and SN-38. This metabolite can be converted to SN38 glucuronide by UDP-glucuronyltransferase (a 1.1 isoenzyme). A recently discovered metabolite is 7-ethyl-10-[4-N-(5-aminovaleric acid)-1-piperidinyl]-carbonyloxycamptothecin (APC), which is generated by the action of cytochrome P450 3A4. Many other unidentified metabolites have also been detected in bile and urine. …Irinotecan is a camptothecin analogue, a prodrug that requires bioactivation to form the active metabolite SN-38. SN-38 is a DNA topoisomerase I inhibitor. Irinotecan undergoes two metabolic pathways in vivo: first, CYP3A4-mediated oxidative metabolism to produce two inactive metabolites, APC or NPC; second, tissue carboxylesterase-mediated hydrolysis to generate SN-38, which is ultimately detoxified by glucuronidation via UGT1A1 to generate SN-38G. The pharmacological properties of irinotecan are also influenced by inter-individual genetic differences in irinotecan activation and inactivation enzymes (e.g., CYP3A4, CYP3A5, UGT1A1), and it competes with many concomitant drugs (e.g., anticonvulsants, St. John's wort, and ketoconazole) for elimination. Furthermore, irinotecan and its metabolites are expelled from cells via various drug transporters (e.g., Pgp, BCRP, MRP1, MRP2). This review highlights the latest research findings on irinotecan activation, transport mechanisms, glucuronidation, and CYP3A-mediated drug interactions, aiming to elucidate its complex pharmacological mechanisms and provide insights for future research on optimizing this promising drug. Irinotecan is a water-soluble precursor of its lipophilic metabolite SN-38. SN-38 is generated from irinotecan via carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidine side chain. SN-38, as a topoisomerase I inhibitor, is approximately 1000 times more potent than irinotecan and has been purified from human and rodent tumor cell lines. In vitro cytotoxicity assays have shown that SN-38 is 2 to 2000 times more potent than irinotecan. However, the area under the plasma concentration-time curve (AUC) of SN-38 is only 2% to 8% of that of irinotecan, and SN-38 binds to plasma proteins at a rate of 95%, while irinotecan binds to plasma proteins at a rate of approximately 50%. Therefore, the exact contribution of SN-38 to Camptosar activity remains unclear. Both irinotecan and SN-38 exist as active lactones and as inactive hydroxy acid anions. A pH-dependent equilibrium exists between these two forms, with acidic pH promoting the formation of the lactone form and alkaline pH favoring the formation of the hydroxy acid anion form. The metabolism of irinotecan to the active metabolite SN-38 is primarily mediated in the liver by carboxylesterases. SN-38 then binds primarily via UDP-glucuronyltransferase 1A1 (UGT1A1) to form the glucuronide metabolite. UGT1A1 activity is reduced in individuals carrying gene polymorphisms that lead to decreased enzyme activity, such as the UGT1A128 polymorphism. Approximately 10% of the North American population is homozygous for the UGT1A128 allele. In a prospective study, irinotecan was administered as monotherapy every 3 weeks, and the results showed that patients homozygous for UGT1A128 had higher SN-38 exposure than patients carrying the wild-type UGT1A1 allele. In in vitro cytotoxicity assays using two cell lines, the activity of SN-38 glucuronide was approximately 1/50 to 1/100 that of SN-38. The distribution of irinotecan in humans has not been fully elucidated. The urinary excretion rate of irinotecan was 11% to 20%; the urinary excretion rate of SN-38 was <1%; and the urinary excretion rate of SN-38 glucuronide was 3%. In two patients, the cumulative bile and urinary excretion rates of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) within 48 hours of irinotecan treatment were approximately 25% (100 mg/m²) to 50% (300 mg/m²).
Irinotecan's known human metabolites include: (2S,3S,4S,5R)-6-[[(19S)-10,19-diethyl-14,18-dioxo-7-(4-piperidin-1-ylpiperidin-1-carbonyl)oxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]ticos-1(21),2,4(9),5,7,10,15(20)-hepten-19-yl]oxy]-3,4,5-trihydroxyoxacyclohexane-2-carboxylic acid and 7-ethyl-10-[4-N-(5-aminovaleric acid)-1-piperidinyl]carbonyloxycamptothecin.

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Biological half-life
Irinotecan's half-life is approximately 6-12 hours. The terminal elimination half-life of the active metabolite SN-38 is 10–20 hours. Following intravenous infusion of irinotecan in humans, plasma concentrations of irinotecan decrease exponentially, with a mean terminal elimination half-life of approximately 6–12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is approximately 10–20 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 are similar to those of the total irinotecan and SN-38 because the lactone and hydroxy acid forms are in equilibrium.

Protein Binding
30%–68% of the irinotecan is bound to protein, primarily albumin. Interactions Pharmacokinetics were evaluated in 190 patients treated with irinotecan (49 smokers and 141 non-smokers, administered intravenously every 3 weeks over 90 minutes). Complete toxicity data were obtained in 134 patients receiving a fixed dose of irinotecan at 350 mg/m² or 600 mg. The area under the dose-normalized plasma concentration-time curve was significantly lower in smokers compared to non-smokers (median, 28.7 vs 33.9 ng·hr/mL/mg; P = .001). Furthermore, smokers experienced a nearly 40% reduction in SN-38 exposure (median 0.54 ng xh/mL/mg vs. 0.87 ng xh/mL/mg; P < .001), and a higher relative conversion of SN-38 to SN-38G (median 6.6 vs. 4.5; P = .006). Hematologic toxicity was significantly reduced in smokers. In particular, the incidence of grade 3-4 neutropenia was 6% in smokers compared to 38% in non-smokers (odds ratio [OR] 0.10; 95% confidence interval 0.02 to 0.43; P < .001). There was no significant difference in the incidence of delayed diarrhea (6% vs. 15%; OR, 0.34; 95% CI, 0.07 to 1.57; P = .149). This study suggests that smoking significantly reduces irinotecan exposure and treatment-induced neutropenia, indicating a potential risk of treatment failure. Although the underlying mechanisms are not fully understood, regulation of CYP3A and the uridine diphosphate glucuronide transferase 1A1 subtype may be partly responsible. Data suggest that further research is necessary to determine whether smokers have a higher risk of treatment failure.
In the treatment of human immunodeficiency virus-associated malignancies, the combination of protease inhibitors and anticancer drugs may lead to potential drug interactions. This study investigated the effect of lopinavir/ritonavir (LPV/RTV) on the pharmacokinetics of irinotecan (CPT11) in seven patients with Kaposi's sarcoma. LPV/RTV combination therapy reduced CPT11 clearance by 47% (11.3±3.5 vs 21.3±6.3 L/h/m², P=0.0008). This effect was associated with an 81% reduction in the AUC of the oxidative metabolite APC (7-ethyl-10-[4-N-(5-aminovaleric acid)-1-piperidinyl]carbonyloxycamptothecin) (P=0.02). LPV/RTV treatment also inhibited the production of SN38 glucuronide (SN38G), with the SN38G/SN38 AUC ratio decreasing by 36% (5.9±1.6 vs 9.2±2.6, P=0.002), consistent with the inhibitory effect of LPV/RTV on UGT1A1. This dual effect resulted in CPT11 being available for SN38 conversion and reduced inactivation on SN38, thereby increasing the AUC of SN38 by 204% under LPV/RTV treatment (P=0.0001). The clinical significance of these significant pharmacokinetic changes warrants further investigation. Irinotecan or CPT-11 [7-ethyl-10-[4-(1-piperidinyl)-1-piperidinyl]carbonyloxycamptothecin] is a derivative of camptothecin used to treat advanced colorectal cancer. It requires carboxylesterase activation to convert to SN-38 (7-ethyl-10-hydroxycamptothecin). Irinotecan and SN-38 are primarily detoxified via two metabolic pathways: the first pathway generates oxidative degradation products APC (7-ethyl-10-[4-N-(5-aminovaleric acid)-1-piperidinyl)carbonyloxycamptothecin] and NPC [7-ethyl-10-(4-amino-1-piperidinyl)carbonyloxycamptothecin], involving cytochrome P450 (3A4 isoenzyme); the second pathway generates SN-38 glucuronide (SN-38G), involving UDP-glucuronyltransferase (UGT). Using human liver microsomes, the interactions of 15 commonly used drugs in colorectal cancer patients with these metabolic pathways were investigated. Only nifedipine significantly affected SN-38 formation, reducing carboxylesterase activity by 50% at 100 μM and by 35% at 10 μM. Three drugs significantly affected SN-38G formation: clonazepam increased UGT activity by 50% at 100 μM and by 30% at 10 μM; nifedipine and vinorelbine inhibited UGT activity by 65% and 55%, respectively, at 100 μM, but had no effect at 10 μM. Five drugs significantly inhibited SN-38 formation at 100 μM: clonazepam (70%), methylprednisolone (50%), nifedipine (80%), omeprazole (85%), and vinorelbine (100%). Only omeprazole and vinorelbine showed significant inhibitory effects at 10 μM (30% and 90%, respectively), while only vinorelbine showed significant effects at 2 μM and 0.5 μM concentrations (70% and 40%, respectively). In summary, potential clinical interactions with irinotecan metabolism are likely primarily with vinorelbine, as it potently inhibits CYP3A4 metabolism of irinotecan at clinically relevant concentrations; the effective concentrations of other drugs are far below those actually reached by patients. Concomitant use with the CYP3A4 and UGT1A1 inhibitor atazanavir sulfate may increase systemic exposure to the active metabolite of irinotecan, SN-38. Physicians should consider this when using these drugs in combination. For more complete data on interactions with irinotecan (12 drugs in total), please visit the HSDB record page.

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In a mouse model of malignant neuroectodermal tumors, 100 mg/kg of irinotecan (CPT-11) (intraperitoneal injection, once a week for 3 weeks) did not cause significant changes in body weight, hematological parameters (white blood cell count, red blood cell count, platelet count), or liver and kidney function indicators (ALT, AST, BUN, creatinine) compared to the control group [1] - Irinotecan (CPT-11) induced apoptosis in mouse peritoneal resident macrophages in vitro, which may be a potential off-target toxicity related to peritoneal immune function [5]

[1]. Antitumoral effect of irinotecan (CPT-11) on an experimental model of malignant neuroectodermal tumor. J Neurooncol. 2002 Feb;56(3):219-26.

[2]. Determinants of the cytotoxicity of irinotecan in two human colorectal tumor cell lines. Cancer Chemother Pharmacol. 2002 Apr;49(4):329-35. Epub 2002 Jan 30.

[3]. Thrombospondin-1 plus irinotecan: a novel antiangiogenic-chemotherapeutic combination that inhibits the growth of advanced human colon tumor xenografts in mice. Cancer Chemother Pharmacol. 2004 Mar;53(3):261-6. Epub 2003 Dec 5.

[4]. A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma. Genome Med. 2016 Oct 31;8(1):116.

[5]. Chemotherapeutic agent CPT-11 eliminates peritoneal resident macrophages by inducing apoptosis. Apoptosis. 2016 Feb;21(2):130-42.

Therapeutic Uses
Irinotecan, in combination with cisplatin, is used for the initial treatment of extensive-stage small cell lung cancer. Irinotecan hydrochloride can be used as monotherapy for patients with recurrent or progressive metastatic colorectal cancer after initial treatment with a fluorouracil-based antitumor regimen. /Irinotecan Hydrochloride/ Irinotecan is being investigated as an effective treatment for metastatic or recurrent cervical cancer. Irinotecan as monotherapy for advanced cervical squamous cell carcinoma has been reported to have an objective response rate of 13-21%. Although no efficacy of irinotecan was observed in a small, uncontrolled phase II study of patients with platinum-resistant advanced cervical squamous cell carcinoma, similar patients responded to the drug in another phase II study. The benefit of combination chemotherapy regimens compared to monotherapy (e.g., cisplatin alone) has not been fully established, and further research is needed to determine the role of irinotecan in the treatment of advanced cervical cancer. /This use is not currently included in the FDA-approved label in the United States/
Irinotecan hydrochloride, in combination with fluorouracil and leucovorin, is used as a first-line treatment for metastatic colorectal cancer or rectal cancer. /Irinotecan Hydrochloride/
The efficacy of irinotecan in pediatric patients has not been established. Results from two open-label, single-arm studies have been evaluated. A phase II trial enrolled 170 children with refractory solid tumors, who received irinotecan at a dose of 50 mg/m² intravenously for 5 consecutive days every 3 weeks. 54 patients (31.8%) experienced grade 3-4 neutropenia. 15 patients (8.8%) experienced neutropenia complicated by fever. 35 patients (20.6%) experienced grade 3-4 diarrhea. The adverse event spectrum was similar to that in adult patients. In another phase II clinical trial involving 21 previously untreated children with rhabdomyosarcoma, irinotecan was administered intravenously at a dose of 20 mg/m² for 5 consecutive days at weeks 0, 1, 3, and 4. This monotherapy was followed by multimodal therapy. Recruitment for the irinotecan monotherapy phase was terminated early due to a high disease progression rate (28.6%) and a high early mortality rate (14%). The adverse event spectrum in this study differed from that in adult patients; the most serious grade 3 or 4 adverse events were dehydration in 6 patients (28.6%), including 5 patients (23.8%) with severe hypokalemia and 3 patients (14.3%) with hyponatremia. Additionally, 5 patients (23.8%) reported grade 3-4 infections (covering all treatment cycles and not causally related). Drug Warning: Captoxa injection should only be used under the supervision of a physician experienced in the use of anticancer chemotherapy drugs. Complications can only be properly managed with adequate diagnostic and treatment facilities. Captoxar can cause early and late diarrhea, the mechanisms of which appear to be different. Both types of diarrhea can be severe. Early diarrhea (occurring during or shortly after captoxar infusion) may be accompanied by cholinergic symptoms such as rhinitis, increased salivation, miosis, lacrimation, sweating, flushing, and hypermotility, which can cause abdominal cramps. Atropine can prevent or relieve early diarrhea and other cholinergic symptoms. Delayed diarrhea (usually occurring 24 hours after captoxar administration) can be life-threatening because it can be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Delayed diarrhea should be treated immediately with loperamide. Patients with diarrhea should be closely monitored, and fluid and electrolyte replacement should be given if dehydration occurs; antibiotics should be used if intestinal obstruction, fever, or severe neutropenia occurs. If severe diarrhea occurs, captoxar should be discontinued and subsequent doses reduced. Severe bone marrow suppression may occur.
Close monitoring is recommended for patients over 65 years of age, as the risk of treatment-related toxicities (such as delayed diarrhea) is increased during irinotecan treatment. Patients receiving irinotecan/fluorouracil/leucovorin should be closely monitored (e.g., assessed weekly), especially during the first treatment cycle, as most treatment-related toxicities leading to early death occur within the first 3–4 weeks. Changes in serum electrolytes and/or acid-base balance, including hyponatremia or hypernatremia, hypokalemia, and/or metabolic acidosis, may be early signs of treatment-related toxicities; patients with abnormal serum sodium, potassium, and/or bicarbonate concentrations, whether or not accompanied by elevated serum urea nitrogen or creatinine concentrations, should be carefully assessed for dehydration and receive aggressive medical intervention, including fluid and electrolyte replacement.
There have been reports of patients receiving capituxa who died from sepsis following severe neutropenia.
In addition to gastrointestinal and hematologic toxicities, other serious adverse reactions can occur in patients receiving irinotecan. Hypersensitivity reactions, including severe anaphylactic or anaphylactoid reactions, have been reported. Renal impairment and acute renal failure are rare, usually occurring in patients with volume depletion due to severe vomiting and/or diarrhea. Cardiovascular events and thromboembolic events have also been reported. For more complete data on drug warnings for irinotecan (19 in total), please visit the HSDB record page.
Pharmacodynamics
Irinotecan is an antitumor enzyme inhibitor primarily used to treat colorectal cancer. Irinotecan is a semi-synthetic derivative of camptothecin. Camptothecin drugs specifically interact with topoisomerase I, a nuclear enzyme that regulates DNA topology and promotes intranuclear processes such as DNA replication, recombination, and repair. In these processes, topoisomerase I relieves torsional stress on DNA by inducing reversible single-strand breaks, allowing a single DNA strand to pass through the break. The 3' end of the broken DNA strand covalently binds to topoisomerase, forming a catalytic intermediate called a cleavable complex. Once DNA is sufficiently relaxed and the strand transfer reaction is complete, DNA topoisomerase rejoins the broken DNA strands to form chemically unchanged topoisomers, allowing transcription to proceed. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex, preventing the rejoining of these single-strand breaks. Current research indicates that irinotecan's cytotoxicity is due to double-strand DNA damage resulting from the interaction of replicase with topoisomerase I, DNA, and the ternary complex formed by irinotecan or SN-38 during DNA synthesis. Mammalian cells cannot effectively repair these double-strand breaks. The extent to which SN-38 contributes to the activity of irinotecan in humans is unclear. Irinotecan exhibits cell cycle specificity (S phase).

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Irinotecan (CPT-11) exerts its anti-tumor effect mainly by inhibiting topoisomerase I, leading to the accumulation of DNA single-strand breaks, and thus inducing tumor cell apoptosis[2]
-Irinotecan (CPT-11), when used in combination with the anti-angiogenic drug TSP-1, showed synergistic anti-tumor activity in a xenograft model of advanced human colon cancer, suggesting that this combination strategy has potential clinical application value[3]

C33H38N4O6

586.68

586.279

C, 67.56; H, 6.53; N, 9.55; O, 16.36

97682-44-5

100286-90-6 (HCl); 136572-09-3 (HCl trihydrate); 143490-53-3 (Lactone Impurity) ; 97682-44-5; 1329502-92-2 (Carboxylate Sodium Salt)

60838

White to yellow solid powder

1.4±0.1 g/cm3

873.4±65.0 °C at 760 mmHg

222-223 °C
222-223 °C
222 - 223 °C

482.0±34.3 °C

0.0±0.3 mmHg at 25°C

1.689

4.35

1

8

5

43

1200

1

C(C1C2C=C(C=CC=2N=C2C3=CC4[C@@](C(OCC=4C(=O)N3CC=12)=O)(O)CC)OC(N1CCC(N2CCCCC2)CC1)=O)C

UWKQSNNFCGGAFS-XIFFEERXSA-N

InChI=1S/C33H38N4O6/c1-3-22-23-16-21(43-32(40)36-14-10-20(11-15-36)35-12-6-5-7-13-35)8-9-27(23)34-29-24(22)18-37-28(29)17-26-25(30(37)38)19-42-31(39)33(26,41)4-2/h8-9,16-17,20,41H,3-7,10-15,18-19H2,1-2H3/t33-/m0/s1

[(19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-7-yl] 4-piperidin-1-ylpiperidine-1-carboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.55 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (3.55 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (3.55 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 30% Propylene glycol , 5% Tween 80 , 65% D5W: 30 mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)