HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
Irinotecan
IRINOTECAN HCL · CPT-11 · CAMPTOSAR · (S)-4,11-Diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl [1,4'-bipiperidine]-1'-carboxylate · Irinotecan(TECANS) · Irinotecan (free Base) · [1,4'-BIPIPERIDINE]-1'-CARBOXYLIC ACID · (19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.0^{2,11}.0^{4,9}.0^{15,20}]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-7-yl 4-(piperidin-1-yl)piperidine-1-carboxylate
Identifikatoren & physikalische Daten
| CAS No. | 100286-90-6 |
|---|---|
| Summenformel | C33H38N4O6 |
| Durchschnittliche Molmasse | 586,7 g/mol |
| Monoisotopische Masse | 586,27913494 g/mol |
| SMILES | CCc1c2c(nc3ccc(OC(=O)N4CCC(N5CCCCC5)CC4)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC |
| InChIKey | UWKQSNNFCGGAFS-XIFFEERXSA-N |
| PubChem CID | 60838 |
| ChEMBL | CHEMBL481 |
| ChEBI | CHEBI:80630 |
| EC No. | 691-567-9 |
| DTXSID | DTXSID1041051 |
Chemische & physikalische Eigenschaften
| XLogP | 3 |
|---|---|
| Polarare Oberfläche (TPSA) | 113 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 8 |
| Frei drehbare Bindungen | 5 |
| Schwere Atome | 43 |
| Formalladung | 0 |
| Komplexität | 1.200 |
| Arzneimittel | Pharmaceuticals -> Listed in ZINC15 |
| LogP (Verteilungskoeffizient) | 3.2 |
| Color/Form | Pale yellow powder |
| Löslichkeit | 1.07e-01 g/LAcetonitrile (Slightly, Heated, Sonicated), DMSO (Slightly), Methanol (Slightly) |
| Human Drugs | Breast FeedingLactationMilk, HumanAntineoplastic AgentsEnzyme InhibitorsTopoisomerase I InhibitorsCytotoxic medicines |
| Schmelzpunkt | 222-223 °C222 - 223 °C222-223° |
| Optical Rotation | Slightly pale yellow needles or crystalline powder from water, mp 256.6 °C. MW 677.18. Specific optical rotation: +67.7 deg at 20 °C/D ( c = 1 in water). UV max (ethanol): 221, 254, 359, 372 nm (epsilon 53800, 36600, 26200, 25300). Slightly soluble in water and organic solvents. pH of aqueous solution = 4. /Hydrochloride trihydrate/ |
| Physical Description | Solid |
| Dissociation Constants | 10.9 |
| Other Experimental Properties | Pale yellow to yellow crystalline powder. MW: 677.19. Slightly soluble in water and organic solvents /Hydrochloride/ |
| Siedepunkt | 873.4±65.0 °C(Predicted) |
| Dichte | 1.40±0.1 g/cm3(Predicted) |
| Lagerbedingungen | Sealed in dry,2-8°C |
| pKa (Säurekonstante) | 11.20±0.20(Predicted) |
| Aggregatzustand | Solid |
| Farbe | White to Brown |
| InChIKey | UWKQSNNFCGGAFS-XIFFEERXSA-N |
| SMILES | N1(C2CCN(C(OC3=CC=C4C(=C3)C(CC)=C3CN5C(C3=N4)=CC3[C@](CC)(O)C(=O)OCC=3C5=O)=O)CC2)CCCCC1 |
| CAS Datenbank | 97682-44-5(CAS DataBase Reference) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]P203, P260, P264, P264+P265, P270, P280, P301+P317, P302+P352, P305+P354+P338, P317, P318, P319, P321, P330, P332+P317, P362+P364, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 9 reports by companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. |
|---|---|
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl irinotecan hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Irinotecan hydrochloride/ |
| Hazard Classes and Categories | Acute Tox. 4 (100%) |
| Shipment Methods and Regulations | /PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/ |
| Lagerbedingungen | Solutions of irinotecan hydrochloride prepared in 5% dextrose injection are physically and chemically stable for up to 24 hours when stored at room temperature (approximately 25 °C) under ambient fluorescent lighting or for up to 48 hours when protected from light and refrigerated at 2-8 °C. For irinotecan hydrochloride solutions prepared in 5% dextrose injection, the manufacturer recommends administration of such drug solutions within 24 hours if refrigerated or within 6 hours if maintained at room temperature because of the potential for microbial contamination during preparation of the admixtures. Solutions of irinotecan hydrochloride prepared in 0.9% sodium chloride are stable for up to 24 hours when stored at room temperature (approximately 25 °C) under ambient fluorescent lighting. The manufacturer states that solutions of irinotecan hydrochloride prepared in 0.9% sodium chloride may occasionally develop visible particulates when refrigerated at 2-8 °Ctherefore, solutions prepared in sodium chloride injection should not be refrigerated but should be stored at room temperature and used within 6 hours. Freezing of commercially available irinotecan hydrochloride for injection concentrate or IV admixtures of the drug may result in formation of a precipitate and should be avoided. |
| Entsorgungsverfahren | SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices./PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/For more Disposal Methods (Complete) data for IRINOTECAN (8 total), please visit the HSDB record page. |
| Preventive Measures | If irinotecan hydrochloride for injection concentrate or a solution of the drug comes in contact with the skin or mucous membranes, the skin should be washed immediately and thoroughly with soap and water or the mucosa should be flushed with copious amounts of water./PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/For more Preventive Measures (Complete) data for IRINOTECAN (21 total), please visit the HSDB record page. |
| Personal Protective Equipment (PPE) | /PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lotstherefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/ |
| Wechselwirkungen | A total of 190 patients (49 smokers, 141 nonsmokers) treated with irinotecan (90-minute intravenous administration on a 3-week schedule) were evaluated for pharmacokinetics. Complete toxicity data were available in a subset of 134 patients receiving 350 mg/sq m or 600 mg flat-fixed dose irinotecan. In smokers, the dose-normalized area under the plasma concentration-time curve of irinotecan was significantly lower (median, 28.7 v 33.9 ng x hr/mL/mgP = .001) compared with nonsmokers. In addition, smokers showed an almost 40% lower exposure to SN-38 (median, 0.54 v 0.87 ng x h/mL/mgP < .001) and a higher relative extent of glucuronidation of SN-38 into SN-38G (median, 6.6 v 4.5P = .006). Smokers experienced considerably less hematologic toxicity. In particular, the incidence of grade 3 to 4 neutropenia was 6% in smokers versus 38% in nonsmokers (odds ratio [OR], 0.1095% CI, 0.02 to 0.43P < .001). There was no significant difference in incidence of delayed-onset diarrhea (6% v 15%OR, 0.3495% CI, 0.07 to 1.57P = .149). This study indicates that smoking significantly lowers both the exposure to irinotecan and treatment-induced neutropenia, indicating a potential risk of treatment failure. Although the underlying mechanism is not entirely clear, modulation of CYP3A and uridine diphosphate glucuronosyltransferase isoform 1A1 may be part of the explanation. The data suggest that additional investigation is warranted to determine whether smokers are at increased risk for treatment failure.The coadministration of protease inhibitors with anticancer drugs in the management of human immunodeficiency virus-related malignancies can cause potential drug-drug interactions. The effect of lopinavir/ritonavir (LPV/RTV) on the pharmacokinetics of irinotecan (CPT11) has been investigated in seven patients with Kaposi's sarcoma. Coadministration of LPV/RTV reduces the clearance of CPT11 by 47% (11.3+/-3.5 vs 21.3+/-6.3 l/h/m(2), P=0.0008). This effect was associated with an 81% reduction (P=0.02) of the AUC (area under the curve) of the oxidized metabolite APC (7-ethyl-10-[4-N-(5-aminopentanoic-acid)-1-piperidino]-carbonyloxycamptothecin). The LPV/RTV treatment also inhibited the formation of SN38 glucuronide (SN38G), as shown by the 36% decrease in the SN38G/SN38 AUCs ratio (5.9+/-1.6 vs 9.2+/-2.6, P=0.002) consistent with UGT1A1 inhibition by LPV/RTV. This dual effect resulted in increased availability of CPT11 for SN38 conversion and reduced inactivation on SN38, leading to a 204% increase (P=0.0001) in SN38 AUC in the presence of LPV/RTV. The clinical consequences of these substantial pharmacokinetic changes should be investigated.Irinotecan or CPT-11 [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] is a derivative of camptothecine used in the treatment of advanced colorectal cancer. It requires activation to SN-38 (7-ethyl-10-hydroxycamptothecine) by carboxylesterase. Irinotecan and SN-38 are detoxified through two major metabolic pathways: the first one leads to oxidative degradation compounds, APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino)carbonyloxycamptothecine] and NPC [7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine], and involves cytochrome P450 (3A4 isoform)the second one leads to SN-38 glucuronide (SN-38G) and involves UDP-glucuronosyltransferase (UGT). Using human hepatic microsomes, ... the interactions of 15 drugs of common use in colorectal cancer patients on these metabolic pathways /were studied/. Only nifedipine had a significant effect on SN-38 formation, decreasing carboxylesterase activity by 50% at 100 microM and 35% at 10 microM. Three drugs had a significant effect on SN-38G formation: clonazepam increased UGT activity by 50% at 100 uM and 30% at 10 microM, and nifedipine and vinorelbine inhibited the activity by 65 and 55% at 100 uM, respectively, with no effect at 10 microM. Five drugs exerted a significant inhibition on SN-38 formation at 100 microM: clonazepam (70%), methylprednisolone (50%), nifedipine (80%), omeprazole (85%), and vinorelbine (100%). Only omeprazole and vinorelbine still exerted a significant inhibition at 10 microM (30 and 90%, respectively), whereas only vinorelbine had a significant effect at 2 and 0.5 microM (70 and 40%, respectively). In conclusion, potential clinical interactions with the metabolism of irinotecan are likely to be important for vinorelbine, which strongly inhibits irinotecan catabolism by CYP3A4 at clinically relevant concentrations, but not for the other drugs, which exert an effect at concentrations not achievable in patients.Coadministration of atazanavir sulfate, a CYP3A4 and UGT1A1 inhibitor has the potential to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into consideration when co-administering these drugs.For more Interactions (Complete) data for IRINOTECAN (12 total), please visit the HSDB record page. |
| Unerwünschte Wirkungen | The adverse effects of irinotecan are primarily due to its active metabolite, SN-38. Common adverse effects include neutropenia, diarrhea, nausea, vomiting, alopecia, and fatigue. Neutropenia associated with irinotecan is usually short-lived but can be severe if diarrhea is also present. If patients have the UGT1A1*28 allele of the UDP-glucuronosyltransferase enzyme that inactivates SN-38 into the SN-38G form, there is decreased glucuronidation into the SN-38G form. The UGT1A1*28 allele is associated with increased diarrhea events of neutropenia because the active form, SN-38, cannot be inactivated as effectively. |
| Toxizitätsübersicht | Life-threatening toxicities can occur even in patients who are in relatively good conditions. When a patient is unable to manage the side effect profile of irinotecan, it limits the therapeutic advantages that come with its use. Most of the irinotecan's side effect profile is due to its active metabolite, SN-38. Researchers have noted higher incidences of toxicity with genetic polymorphisms to the UDP-glucuronosyltransferase 1A1 gene. A particular polymorphism, UDP1A1*28, decreases the inactivation of SN-38, causing adverse toxic effects. Patients with Gilbert disease, a syndrome of mildly decreased levels of UDP-glucuronyltransferase provoked at times of stress, suffer toxic side effects more commonly than patients not diagnosed with Gilbert disease. |
| Medical Surveillance | /PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/ |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ In U.S. phase 1 trials, single doses of up to 345 mg/sq m of irinotecan were administered to patients with various cancers. Single doses of up to 750 mg/sq m of irinotecan have been given in non-U.S. trials. The adverse events in these patients were similar to those reported with the recommended dosage and regimen. There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhea./SIGNS AND SYMPTOMS/ In addition to GI and hematologic toxicity, other severe adverse effects have occurred in patients receiving irinotecan. Hypersensitivity reactions, including severe anaphylactic or anaphylactoid reactions, have been reported. Renal impairment and acute renal failure have occurred rarely, usually in patients who became volume-depleted from severe vomiting and/or diarrhea. Cardiovascular and thromboembolic events also have been reported./SIGNS AND SYMPTOMS/ Close monitoring is advised in patients older than 65 years of age because of increased risk of treatment-related toxicity, such as late diarrhea, during irinotecan therapy. Patients receiving irinotecan/fluorouracil/leucovorin therapy should be monitored closely (e.g., weekly assessment), particularly during the first cycle of treatment, since most of the treatment-related toxicities leading to early death occurred 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 an early indication of treatment-related toxicitypatients with abnormalities in serum sodium, potassium, and/or bicarbonate concentrations, with or without concomitant elevations in serum BUN or creatinine concentrations, should be evaluated carefully for dehydration and receive aggressive medical management, including fluid and electrolyte replacement./SIGNS AND SYMPTOMS/ Deaths due to sepsis following severe neutropenia have been reported in patients treated with Camptosar.For more Human Toxicity Excerpts (Complete) data for IRINOTECAN (13 total), please visit the HSDB record page. |
| Drug Induced Liver Injury | Drug-Induced Liver Injury Severity and Toxicity (DILIst)irinotecanDILI PositiveIntravenousDOI:10.1016/j.drudis.2019.09.022 |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Acute Exposure/ Groups of breast cancer-bearing dark agouti (DA) rats were treated with 100, 150 or 200 mg/kg doses of irinotecan or vehicle control daily for two days, and killed at 6, 24, 72 or 96 hr after treatment. Apoptosis and morphometry were examined in both the small and large intestines. Histopathology and goblet cell numbers were recorded. ... Irinotecan increased apoptosis and caused villous atrophy and crypt hypoplasia in the small intestine, and increased apoptosis, crypt hypoplasia, crypt dilation and mucus secretion in the large intestine. Irinotecan at 100 and 150 mg/kg caused crypt hypoplasia at 6 and 24 hr, with rebound hyperplasia at 72 and 96 hr. At 200 mg/kg, irinotecan caused a more pronounced crypt hypoplasia earlier and all animals died by 96 hr. Apoptosis peaked at 6 hr and remained elevated over the remainder of the time-points. This was not dose-dependent. Irinotecan at all doses altered colonic, but not jejunal, goblet cells. Irinotecan increased colonic mucus secretion. ... Irinotecan causes diarrhea by inducing apoptosis and hypoproliferation in both the small and large intestines, and causes colonic damage with changes in goblet cells and mucin secretion./LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Rats were ... administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per week for 13 weeks (in separate studies, the 25 mg/kg dose produced an irinotecan Cmax and AUC that were about 7.0 times and 1.3 times the respective values in patients administered 125 mg/sq m weekly) and were then allowed to recover for 91 weeks. Under these conditions, there was a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Irinotecan was teratogenic in rats at doses greater than 1.2 mg/kg/day (which in separate studies produced an irinotecan Cmax and AUC about 2/3 and 1/40th, respectively, of the corresponding values in patients administered 125 mg/sq m) and in rabbits at 6.0 mg/kg/day (about one-half the recommended human weekly starting dose on a mg/sq m basis). Teratogenic effects included a variety of external, visceral, and skeletal abnormalities. Irinotecan administered to rat dams for the period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Administration of 6 mg/kg/day intravenous irinotecan to rats (which in separate studies produced an irinotecan Cmax and AUC about 2 and 0.2 times, respectively, the corresponding values in patients administered 125 mg/sq m) and rabbits (about one-half the recommended human weekly starting dose on a mg/sq m basis) during the period of organogenesis, is embryotoxic as characterized by increased post-implantation loss and decreased numbers of live fetuses.For more Non-Human Toxicity Excerpts (Complete) data for IRINOTECAN (6 total), please visit the HSDB record page. |
| Populations at Special Risk | Because irinotecan often causes neutropenia, leukopenia, and anemia, which can be severe, the drug should not be used in patients with severe bone marrow failure. Because irinotecan hydrochloride for injection concentrate contains sorbitol, the drug should not be given to patients with hereditary fructose intolerance.Close monitoring is advised in patients older than 65 years of age because of increased risk of treatment-related toxicity, such as late diarrhea, during irinotecan therapy. ...... Uridine-diphosphoglucuronosyl transferase 1A1 (UGT1A1)*28 polymorphism reduces UGT1A1 enzyme activity, which may lead to severe toxicities in patients who receive irinotecan. This study was conducted to assess the influence of this polymorphism on the efficacy and toxicity of irinotecan treatment in Chinese patients with metastatic colorectal carcinoma. In total, 128 patients with metastatic colorectal carcinoma who had received previous treatment with irinotecan plus 5-fluorouracil/leucovorin were analyzed retrospectively. Genomic DNA samples were obtained from patients' leukocytes, and genotypes were determined by analyzing the sequence of TATA boxes in the UGT1A1 gene. The influence of the UGT1A1*28 polymorphism on toxicity and treatment outcome was analyzed. Approximately 20% of patients were identified with the UGT1A1*28 polymorphism, including 15.6% (n = 20 patients) with the thymine-adenine (TA)6/TA7 genotype and 4.7% (n = 6 patients) with the TA7/TA7 genotype. The remaining 79.7% of patients (n = 102) had wild type TA6/TA6. Marked increases in grade 3 or 4 neutropenia (53.8% vs 4.9%P < .01), neutropenic fever (38.5% vs 3.9%P < .01), diarrhea (26.9% vs 5.9%P < .01), and pretreatment bilirubin level (23.1% vs 8.8%P = .04) were observed in patients who had the TA6/TA7 or TA7/TA7 genotypes. Patients' pretreatment bilirubin levels correlated well with irinotecan-induced neutropenia (P < .01). It was noted that, although the requirement for irinotecan dose reduction was significantly greater in patients who had this genetic variant (42.3% vs 12.7%P < .01), it did not affect the response rate to irinotecan-based chemotherapy (42.3% vs 45.1%P = .80), and it did not significantly affect progression-free survival (10 months vs 11 monthsP = .94) or overall survival (19 months vs 18 monthsP = .84). The current data suggested that the UGT1A1*28 polymorphism may be a key determinant for predicting irinotecan-induced severe toxicities without affecting treatment outcome for patients with metastatic colorectal carcinoma.... The association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea /were examined/. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 L/hrP=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%odds ratio, 0.1595% confidence interval, 0.04-0.61P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%odds ratio, 1.8795% confidence interval, 0.49-7.05P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted. |
| Antidote and Emergency Treatment | Emergency and supportive measures. Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. /Antineoplastic agents/Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. /Antineoplastic agents/Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antineoplastic agents/Enhanced elimination. Because of the rapid intracellular incorporation of most of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/ |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during Lactation |
| RTECS-Nr. | DW1061000 |
| R-Sätze (R) | 22 |
| Gefahrensymbole | Xn |
| Gefahrstoffdaten | 97682-44-5(Hazardous Substances Data) |
Anwendungen & Verwendung
Verwenden
Irinotecan is a topoisomerase I inhibitor for LoVo cells and HT-29 cells with IC50 of 15.8 μM and 5.17 μM, respectively