Related Searches: Cytidine, 2'-deoxy-2',2'-difluoro-, Cytidine,5'-deoxy-5-fluoro-, 2',3'-diacetate, Cytidine,2',3'-dideoxy-, 2-Deoxy-D-glucose, 2-Deoxy-D-ribose, View all

Cytidine, 2'-deoxy-2',2'-difluoro-(CAS No. 95058-81-4)

Cytidine, 2'-deoxy-2',2'-difluoro- C9H11F2N3O4 (cas 95058-81-4) Molecular Structure

95058-81-4 Structure

Identification and Related Records

Cytidine, 2'-deoxy-2',2'-difluoro-
【CAS Registry number】
Cytidine, 2-deoxy-2,2-difluoro-2-Deoxy-.beta.-D-2,2-difluorocytidine
Gemcitabine [USAN:BAN:INN]
LY 188011
LY188011 hydrochloride
Cytosine, 1-(2-deoxy-2,2-difluoro-beta-D-erythro-pentofuranosyl)-
Gemcitabine hydrochloride [USAN]
2-Deoxy-2,2-difluorocytidine monohydrochloride
2(1H)-Pyrimidinone, 4-amino-1-(2-deoxy-2,2-difluoro-D-erythro-pentofuranosyl)-
2',2'-Difluorodeoxycytidine(Gemcitabine base)
【Molecular Formula】
C9H11F2N3O4 (Products with the same molecular formula)
【Molecular Weight】
【Canonical SMILES】
【Isomers smiles】
【MOL File】

Chemical and Physical Properties

white powder
1.84 g/cm3
【Melting Point】
168.64 °C
【Boiling Point】
482.7 °C at 760 mmHg
【Refractive Index】
【Flash Point】
245.7 °C
In water, 5.13X10+4 mg/L at 25 deg C (est)
Crystals from water, pH = 8.5
【Spectral properties】
Specific optical rotation: +425.36 deg at 365 deg C; + 71.51 deg at 25 deg C/D (c = 0.96 in methanol)
UV Max (ethanol): 234, 268 (epsilon 7810, 8560
【Computed Properties】
Molecular Weight:263.198146 [g/mol]
Molecular Formula:C9H11F2N3O4
H-Bond Donor:3
H-Bond Acceptor:6
Rotatable Bond Count:2
Tautomer Count:3
Exact Mass:263.071762
MonoIsotopic Mass:263.071762
Topological Polar Surface Area:108
Heavy Atom Count:18
Formal Charge:0
Isotope Atom Count:0
Defined Atom Stereocenter Count:3
Undefined Atom Stereocenter Count:0
Defined Bond Stereocenter Count:0
Undefined Bond Stereocenter Count:0
Covalently-Bonded Unit Count:1
Feature 3D Acceptor Count:4
Feature 3D Donor Count:4
Feature 3D Ring Count:2
Effective Rotor Count:3
Conformer Sampling RMSD:0.6
CID Conformer Count:12

Safety and Handling

【Hazard Codes】
Xn: Harmful;Xi: Irritant;
【Risk Statements】
【Safety Statements 】

Hazard Codes:?HarmfulXn,?IrritantXi
Risk Statements: 21-36/38-46-62-63?
R21:Harmful in contact with skin.?
R36/38:Irritating to eyes and skin.?
R46:May cause heritable genetic damage.?
R62:Risk of impaired fertility.?
R63:Possible risk of harm to the unborn child.
Safety Statements: 25-26-36/37-53?
S25:Avoid contact with eyes.?
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.?
S36/37:Wear suitable protective clothing and gloves.?
S53:Avoid exposure - obtain special instructions before use.
Human systemic effects When heated to decomposition it emits toxic vapors of NOx and F?.

Parenteral gemcitabine for injection, for IV infusion: 200 mg (of gemcitabine) Gemzar (with mannitol), Lilly. One g (of gemcitabine) Gemzar (with mannitol), Lilly.
【Exposure Standards and Regulations】
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl gemcitabine hydrochloride approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Gemcitabine hydrochloride/
【Other Preventative Measures】
/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/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Appropriate engineering controls should be in place to protect the drug product from microbial contamination and to protect personnel and the environment from the potential hazards of the product. These engineering controls should be maintained according to applicable regulations and standards. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Biological safety cabinets should be cleaned and disinfected regularly to ensure a proper environment for preparation of sterile products. For routine cleanups of surfaces between decontaminations, water should be used (for injection or irrigation) with or without a small amount of cleaner. If the contamination is soluble only in alcohol, then 70% isopropyl or ethyl alcohol may be used in addition to the cleaner. In general, alcohol is not a good cleaner, only a disinfectant, and its use in a biohazard cabinet should be limited. The biohazard cabinet should be disinfected with 70% alcohol before any aseptic manipulation is begun. The excessive use of alcohol should be avoided in biohazard cabinets where air is recirculated ... because alcohol vapors may build up in the cabinet. A lint-free, plastic-backed disposable liner may be used in the biological safety cabinet to facilitate spill cleanup. ... If used, the liner should be changed frequently ... /or/ whenever it is overtly contaminated. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The biological safety cabinets should be decontaminated on a regular basis (ideally at least weekly) and whenever there is a spill or the biological safety cabinet is moved or serviced, including for certification. ... Currently, no single reagent will deactivate all known hazardous drugs; therefore, decontamination of a biological safety cabinet used for such drugs is limited to removal of contamination from a nondisposable surface (the cabinet) to a disposable surface (eg, gauze or towels) by use of a good cleaning agent that removes chemicals from stainless steel. The cleaning agent selected should have a pH approximating that of soap and be appropriate for stainless steel. Cleaners containing chemicals such as quaternary ammonium compounds should be used with caution, because they may be hazardous to humans and their vapors may build up in any biological safety cabinet where air is recirculated. Similar caution should be used with any pressurized aerosol cleaner; spraying a pressurized aerosol into a biological safety cabinet may disrupt the protective containment airflow, damage the high efficiency particulate air filter, and cause an accumulation of the propellant within a biological safety cabinet where air is recirculated, resulting in a fire and explosion hazard. During decontamination, the operator should wear a disposable closed front gown, disposable latex gloves covered by disposable utility gloves, safety glasses or goggles, a hair covering, and a disposable respirator, because the glass shield of the biological safety cabinet occasionally must be lifted. The blower must be left on, and only heavy toweling or gauze should be used in the biological safety cabinet to prevent it from being "sucked" up the plenum and into the high efficiency particulate air filter. Decontamination should be done from top to bottom (areas of lesser contamination to greater) by applying the cleaner, scrubbing, and rinsing thoroughly with distilled or deionized water. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The high efficiency particulate air filters /or other exhaust scrubbing system/ of the biohazard cabinet must be replaced whenever they restrict required airflow velocity or if they are overtly contaminated (eg, by a breach in technique that causes hazardous drug to be introduced onto the clean side of the supply high efficiency particulate air filter). Personnel and environmental protection must be maintained during replacement of a contaminated high efficiency particulate air filter. Because replacement of a high efficiency particulate air filter generally requires breaking the integrity of the containment aspect of the cabinet, this procedure may release contamination from the filter into the pharmacy or intravenous preparation area if carried out in an inappropriate manner. Before replacement of a high efficiency particulate air filter contaminated with hazardous drugs, the biological safety cabinet service agent should be consulted for a mutually acceptable procedure for replacing and subsequently disposing of a contaminated high efficiency particulate air filter. One procedure would include moving the biological safety cabinet to a secluded area or using plastic barriers to segregate the contaminated area. Protective clothing and equipment must be used by the servicer. The biological safety cabinet should be decontaminated before filter replacement. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During removal of gloves, ... avoid touching the inside of the glove or the skin with the contaminated glove fingers. ... The worker should wear a protective disposable gown made of lint free, low-permeability fabric with a solid front, long sleeves, and tight-fitting elastic or knit cuffs when preparing hazardous drugs. Washable garments are immediately penetrated by liquids and therefore provide little, if any protection. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ When double gloving, one glove should be placed under the gown cuff and one over. The glove-gown interface should be such that no skin on the arm or wrist is exposed. Gloves and gowns should not be worn outside the immediate preparation area. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Eyewash fountains should be available in areas where hazardous drugs are routinely handled. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Although noninjectable dosage forms of hazardous drugs contain varying proportions of drug to nondrug (nonhazardous) components, there is potential for personnel exposure and environmental contamination with the hazardous components. Procedures should be developed to avoid the release of aerosolized powder or liquid into the environment during manipulation of these drugs. Drugs designated as hazardous should be labeled or otherwise identified as such to prevent their improper handling. Tablet and capsule forms of these drugs should not be placed in automated counting machines, which subject them to stress and may introduce powdered contaminants into the work area. During routine handling of hazardous drugs and contaminated equipment, workers should wear one pair of gloves of good quality and thickness. The counting and pouring of hazardous drugs should be done carefully, and clean equipment dedicated for use with these drugs should be used. ... When hazardous drug tablets in unit-of-use packaging are being crushed, the package should be placed in a small sealable plastic bag and crushed with a spoon or pestle; caution should be used not to break the plastic bag. Disposal of unused or unusable oral or topical dosage forms of hazardous drugs should be performed in the same manner as for hazardous injectable dosage forms and waste. ... Hazardous drug work areas should have a sink (preferably with an eyewash fountain) and appropriate first aid equipment to treat accidental skin or eye contact according to the protocol. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ A distinctive warning label with an appropriate CAUTION statement should be attached to all hazardous drug materials, consistent with state laws and regulations. This would include, for example, syringes, IV containers, containers of unit-dose tablets and liquids, prescription vials and bottles, waste containers, and patient specimens that contain hazardous drugs. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Supplies of disposable gloves and gowns, safety glasses, disposable plastic-backed absorbent liners, gauze pads, hazardous waste disposal bags, hazardous drug warning labels, and puncture-resistant containers for disposal of needles and ampuls should be conveniently located for all areas where hazardous drugs are handled. Assembling a "hazardous drug preparation and administration kit" is one way to furnish nursing and medical personnel with the materials needed to reduce the risk of preparing and administering a hazardous drug. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Prospective temporary and permanent employees who may be required to work with hazardous drugs should be so notified and should receive adequate information about the policies and procedures pertaining to their use. This notification should be documented during the interview process and retained as part of the employment record for all employees. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All personnel involved with the transportation, preparation, administration, and disposal of cytotoxic and hazardous substances should continually be updated on new or revised information on safe handling of cytotoxic and hazardous substances. Policies and procedures should be updated accordingly. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The work area should be designed to provide easy access to those items necessary to prepare, label, and transport final products; contain all related waste; and avoid inadvertent contamination of the work area. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Each health-care setting should have an established first aid protocol for treating cases of direct contact with hazardous drugs, many of which are irritating or caustic and can cause tissue destruction. Medical care providers in each setting should be contacted for input into this protocol. The protocol should include immediate treatment measures and should specify the type and location of medical follow-up and work-injury reporting. Copies of the protocol, highlighting emergency measures, should be posted wherever hazardous drugs are routinely handled. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Only individuals trained to administer hazardous drugs should be allowed to perform this function. Training programs should contain information on the therapeutic and adverse effects of these drugs and the potential, long term health risk to personnel handling these drugs. Each individual's knowledge and technique should be evaluated before administration of these drugs. This should be done by written examination and direct observation of the individual's performance. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The danger to health-care personnel from handling a hazardous drug stems from a combination of its inherent toxicity and the extent to which workers are exposed to the drug in the course of carrying out their duties. This exposure may be through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches), inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic agents/
【Protective Equipment and Clothing】
/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 lots; therefore, 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/

?Gemcitabine (CAS NO.95058-81-4) is also named as 2',2'-Difluorodeoxycytidine ; 2'-Deoxy-2',2'-difluorocytidine ; CCRIS 8984 ; DDFC ; DFdC ; DFdCyd ; Gemcitabina ; Gemcitabina [INN-Spanish] ; Gemcitabine ; Gemcitabinum ; Gemcitabinum [INN-Latin] ; HSDB 7567 ; LY 188011 ; NSC 613327 ; UNII-B76N6SBZ8R .

【Octanol/Water Partition Coefficient】
log Kow = -2.01 (est)
【Disposal Methods】
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/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The gown should be removed and placed in a sealable container before removal of the inner gloves. The inner gloves should be removed last and placed in the container with the gown. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Hazardous drug waste should be placed in specially marked (specifically labeled CAUTION: HAZARDOUS CHEMICAL WASTE) thick plastic bags or leakproof containers. These receptacles should be kept in all areas where the drugs are commonly used. All and only hazardous drug waste should be placed in them. Receptacles used for glass fragments, needles, and syringes should be puncture resistant. Hazardous drug waste should not be mixed with any other waste. Waste containers should be handled with uncontaminated gloves. ... Gloves, gowns, drug vials, etc, should be sealed in specially labeled (CAUTION: HAZARDOUS CHEMICAL WASTE) thick plastic bags or leakproof containers. ... All hazardous waste collected from drug preparation and patient-care areas should be held in a secure place in labeled, leakproof drums or cartons (as required by state or local regulation or disposal contractor) until disposal. This waste should be disposed of as hazardous or toxic waste in an EPA-permitted state-licensed hazardous waste incinerator. Transport to an offsite incinerator should be done by a contractor licensed to handle and transport hazardous waste. ... If access to an appropriately licensed incinerator is not available, transport to and burial in an EPA-licensed hazardous waste dump site is an acceptable alternative. While there are concerns that destruction of carcinogens by incineration may be incomplete, newer technologies and stringent licensing criteria have improved this disposal method. ... Chemical deactivation of hazardous drugs should be undertaken only by individuals who are thoroughly familiar with the chemicals and the procedures required to complete such a task. The IARC recently published a monograph describing methods for chemical destruction of some cytotoxic (antineoplastic) drugs in the laboratory setting. The chemicals and equipment described, however, are not generally found in the clinical setting, and many of the deactivating chemicals are toxic and hazardous. Most procedures require the use of a chemical fume hood. The procedures are generally difficult, and the deactivation is not always complete. Serious consideration should be given to the negative aspects of chemical deactivation before one commits to such a course of action. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Regulatory agencies such as the EPA and state solid and hazardous waste agencies and local air and water quality control boards must be consulted regarding the classification and appropriate disposal of drugs that are defined as hazardous or toxic chemicals. EPA categorizes several of the antineoplastic agents as toxic wastes, while many states are more stringent and include as carcinogens certain cytotoxic drugs and hormonal preparations. EPA also allows exemptions from toxic waste regulations for small quantity generators, whereas certain states do not. It is critical to research these regulations when disposal procedures are being established. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If the biological safety cabinets is equipped with a drainpipe and valve, it may be used to collect rinse water. The collection vessel used must fit well around the drain valve and not allow splashing. Gauze may be used around the connection to prevent aerosol from escaping. The collection vessel must have a tight fitting cover, and all rinse water (gauze, if used) must be disposed of as contaminated waste. /Antineoplastic agents/

Use and Manufacturing

【Use and Manufacturing】
Methods of Manufacturing

Preparation: L.W. Hertel, GB 2136425; idem, US 4808614 (1984, 1989 both to Lilly)
The acetonide of 2,3-dihydroxypropanal (chiron- from mannitol) undergoes a Reformatsky reaction with ethyl 2,2-dibromo-2-fluoroacetate to yield the classic alcohol product, which is then benzylated to protect the generated OH group. Treatment with acid removes the acetonide group and the resulting diol forms a lactone with the gamma-OH function. The free OH is benzylated (protection) and the lactone carbonyl reduced to form a mixture of isomers of 3,3-difluoro-4,5-di(benzyloxy)-2-furanol and the free OH is converted to a mesyl ester (I) with methanesulfonyl chloride and base. Cysteine is reacted with trimethylsilyl chloride to silylate the hydroxyl and amino groups (II). Compound I reacts with II, accompanied by loss of the mesyl group and, after removal of the benzyloxy groups with ammonia, yields the title compound.

Biomedical Effects and Toxicity

【Pharmacological Action】
- Antimetabolites that are useful in cancer chemotherapy.
- Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.
- Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.
- Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging.
- Drugs used to potentiate the effectiveness of radiation therapy in destroying unwanted cells.
【Therapeutic Uses】
Gemcitabine in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after the failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines are clinically contraindicated. /Included in US product label/
Gemcitabine is indicated as first-line therapy for locally advanced (nonresectable stage II or III) or metastatic (stage IV) adenocarcinoma of the pancreas. It is also indicated as second-line therapy for patients who have previously been treated with fluorouracil. Treatment with gemcitabine is primarily palliative. /Included in US product label/
Gemcitabine is indicated in combination with cisplatin as a first-line therapy for inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) non-small cell lung carcinoma. /Included in US product label/
Gemcitabine is indicated for the treatment of locally advanced, unresectable, or metastatic biliary tract (ie, cholangiocarcinoma, biliary tree carcinoma, bile duct carcinoma) and gall bladder carcinomas. /Not included in US product label/
Gemcitabine is indicated for treatment of metastatic bladder (urothelial) carcinoma, based on response rates (both complete and partial responses) achieved in clinical trials. /Not included in US product label/
Gemcitabine is indicated, alone or in combination with other chemotherapeutic agents, as reasonable medical therapy at some point in the management of patients with advanced or relapsed epithelial ovarian carcinoma (evidence rating: IIID). /Not included in US product label/
Gemcitabine is indicated, alone or in combination with other agents, for the treatment of relapsed Hodgkin's and non-Hodgkin's lymphomas (T-cell and B-cell). /Not included in US product label/
Gemcitabine is indicated for the treatment of relapsed/refractory, progressive, metastatic, or non-seminomatous gonadal (i.e., testicular, ovarian) and extragonadal germ cell tumors. /Not included in US product label/
【Biomedical Effects and Toxicity】
Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Clearance was affected by age and gender. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations.
Protein binding /of gemcitabine/ is very low, less than 10%.
It is not known wether gemcitabine or its metabolites are distributed into breast milk.
/Elimination is/ renal. 92 to 98% of a single dose of radiolabeled gemcitabine (1000 mg per square meter of body surface area, given over 30 minutes to five patients) was recovered within 1 week, primarily as the inactive uracil metabolite (approximately 89% of the excreted dose) and secondarily as unchanged gemcitabine (less than 10% of the excreted dose).
/Investigators/ determined whether gemcitabine or its metabolites would accumulate during repeated administration. Gemcitabine was administered over two courses with each course consisting of a 30-min infusion at 1000 mg/sq m weekly for 3 weeks followed by 1 week of rest. In 14 patients we evaluated eventual accumulation by comparing the concentrations in blood samples taken before, and at 30 and 60 min after the start of infusion on days 1, 8 and 15, in both cycles. At the end of the infusion gemcitabine concentrations at day 1 of both courses varied between 18 and 77 uM and at day 15 between 13 and 90 uM. The mean ratios day 8/day 1 and day 15/day 1 varied from 0.94 to 1.18. For the inactive metabolite 2',2'-difluoro-2'-deoxyuridine (dFdU) these values varied between 54 and 152 uM and 55 and 157, respectively, and the ratios from 0.96 to 1.08. The concentration of the active metabolite of gemcitabine, gemcitabine triphosphate (dFdCTP) in peripheral white blood cells, ranged between 37 and 283 pmol/1.0 X 10(6) cells at the end of infusion on day 1 and 35 and 115 pmol/1.0 X 10(6) cells on day 15. Potential accumulation was evaluated using a mixed effects model and no evidence was observed of accumulation for either gemcitabine or its metabolites. [de Lange S, van der Born K et al; Eur J Clin Pharmacol 61 (11): 843-9 (2005)] PubMed Abstract
In this study, the plasma pharmacokinetics of gemcitabine and its inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU), were investigated in dogs after intravenous bolus gemcitabine doses of 3, 10, and 30 mg/kg. Furthermore, the intracellular accumulation of the active metabolite gemcitabine triphosphate, as a surrogate pharmacodynamic endpoint, was also determined in vitro in canine melanoma cells. Gemcitabine was characterized by linear kinetics, while dFdU dose proportionality remains unknown. The average gemcitabine clearance was 0.560 L/ and volume of distribution at steady-state of 1.27 L/kg. The average terminal elimination half-life, depending on dose, ranged from 1.75 to 3.23 hr. Plasma concentrations of dFdU peaked at approximately 2 hr post-dosing. In vitro intracellular gemcitabine triphosphate accumulation was saturated with increasing extracellular gemcitabine concentrations. [Freise KJ, Martin-Jimenez T; J Vet Pharmacol Ther 29 (2): 137-45 (2006)] PubMed Abstract
In this study, the plasma pharmacokinetics (PKs) of gemcitabine and dFdU are further explored after gemcitabine doses of 10, 30, and 60 mg/kg administered by intravenous infusion with a loading dose /to dogs/. Gemcitabine displayed linear PKs, while the kinetics of 2',2'-difluorodeoxyuridine (dFdU) were not dose proportional. The overall clearance, volume of distribution at steady-state, and terminal elimination half-life (t(1/2)) for gemcitabine were 0.421 L/, 0.822 L/kg, and 1.49 hr, respectively. Plasma concentrations of dFdU peaked at approximately 2 hr postdosing and had a t(1/2) of 14.9 hr. [Freise KJ, Martin-Jimenez T; J Vet Pharmacol Ther 29 (2): 147-52 (2006)] PubMed Abstract
The current study was performed in nonhuman primates to determine the plasma and CSF pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine (dFdU) following i.v. administration. Gemcitabine, 200 mg/kg, was administered i.v. over 45 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion for determination of gemcitabine and dFdU concentrations. ... Plasma elimination was rapid with a mean t1/2 of 8 +/- 4 min (mean +/- SD) for gemcitabine and 83 +/- 8 min for dFdU. Gemcitabine total body clearance (ClTB) was 177 +/- 40 mLl/min per kg and the Vdss was 5.5 +/- 1.0 L/kg. The maximum concentrations (Cmax) and areas under the time concentration curves (AUC) for gemcitabine and dFdU in plasma were 194 +/- 64 uM and 63.8 +/- 14.6, and 783 +/- 99 uM and 1725 +/- 186, respectively. The peak CSF concentrations of gemcitabine and dFdU were 2.5 +/- 1.4 uM and 32 +/- 41 uM, respectively. The mean CSF:plasma ratio was 6.7% for gemcitabine and 23.8% for dFdU. There is only modest penetration of gemcitabine into the CSF after i.v. administration. [Kerr J, Berg S et al; Cancer Chemother Pharmacol 47 (5): 411-4 (2001)] PubMed Abstract

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