Floxuridine

Pharmaceuticals -> Anti infectives for systemic use -> Antivirals for systemic use

Pharmaceuticals -> Listed in ZINC15

log Kow = -1.16

-1.4

-1.16

Crystals from butyl acetate

WHITE TO OFF-WHITE SOLID

1 g in about 4.5 ml isopropanol, about 7.5 ml methanol, about 12 ml alcohol, about 27 ml acetone; insol in chloroform, ether, and benzene

4.08e+01 g/L

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

302 to 304 °F (NTP, 1992)

150-151 °C

150.5 °C

Crystals from butyl acetate, mp 150-151 °C. Specific optical rotation at 25 °C for D (sodium) line = -21 deg (c = 2 in water) /alpha-Anomer/

Specific optical rotation for D (sodium) line = +37 deg (water); +48.6 deg (DMF)

Inhibits DNA synthesis. (NTP, 1992)

Solid

7.44

pKa = 7.44 (imide nitrogen)

Danger

H301 (96.1%): Toxic if swallowed [Danger Acute toxicity, oral]

P203, P264, P270, P280, P301+P316, P318, P321, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 51 reports by companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl floxuridine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Floxuridine sterile powder should be protected from light and stored at 15-30 °C. In the dry state, floxuridine has an expiration date of 3 years following the date of manufacture. Reconstituted floxuridine injection should be stored at 2-8 °C and used within 2 weeks.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/

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 FLOXURIDINE (8 total), please visit the HSDB record page.

/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/

For more Preventive Measures (Complete) data for FLOXURIDINE (19 total), please visit the HSDB record page.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

/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/

Leukopenic and/or thrombocytopenic effects of floxuridine may be increased with concurrent or recent therapy /with blood dyscrasia-causing medications/ if these medications cause the same effects; dosage adjustment of floxuridine, if necessary, should be based on blood counts.

Additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively /with floxuridine/.

Because normal defense mechanisms may be suppressed by floxuridine therapy, the patients antibody response to killed virus vaccines may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patients ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year.

Because normal defense mechanisms may be suppressed by floxuridine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patients antibody repose to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematological status and only with the knowledge and consent of the physician managing the floxuridine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patients ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members.

Serum aminotransferase elevations occur in a high proportion of patients given floxuridine by infusion into the hepatic artery, the reported rates ranging from 25% to 100%. These elevations are generally mild to moderate in severity and resolve with stopping therapy. "Chemical hepatitis," however, not infrequently is a cause of dose modification or delay in cycles of treatment. In addition, prolonged or repeated hepatic arterial infusions of FUDR can cause acalculous cholecystitis and multiple biliary strictures that can cause jaundice and a chronic sclerosing cholangitis-like syndrome. Between 5% and 25% of patients treated with hepatic arterial infusions of FUDR will develop symptomatic biliary strictures with pain and jaundice. These typically arise after 2 to 6 months of therapy, but can appear later, even more than a year after initiating FUDR therapy. The biliary strictures typically affect central bile ducts in the area of the porta hepatis, generally in and around the bifurcation of the common hepatic duct. Similar inflammation and fibrosis account for the acalculous cholecystitis that can occur with FUDR therapy, but which can be avoided by cholecystectomy at the time of hepatic resection of metastases or placement of the intraarterial infusion pump. The biliary strictures generally improve with stopping therapy, but can progress or require endoscopic or surgical intervention. Deaths from progressive biliary strictures and cholestatic liver injury have been described and can be a major cause of death among survivors of this metastatic tumor. The frequency of biliary strictures after FUDR therapy may be decreased by concurrent administration of dexamethasone and avoided by monitoring with hepatic and biliary imaging. However, the many complications of hepatic arterial infusion chemotherapy have decreased enthusiasm for this therapy, particularly with newer, more potent systemic antineoplastic agents.

/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/

5-Fluorodeoxyuridine was evaluated for genotoxicity in vitro in human Passage 23 WI-38 fibroblasts exposed for 90 minutes to concentrations of 1X10E-6, 1X10E-5, 1X10E-4, 1X10E-3, and 1X10E-2 M test compound in the presence of 1 microCi/ml of 3H-thymidine (6.7 Ci/ml), followed by exposure to only 3H-thymidine for 3 hours. The rate of unscheduled DNA synthesis (UDS) in hepatocytes was determined by measuring the extent of incorporation of labeled thymidine into DNA, using a scintillation counter; results were expressed per unit of DNA. The rate of UDS in treated cell cultures ranged from 0.34-1.67 times that of the negative control, indicating that the test compound was negative for UDS in human fibroblasts under the conditions of this assay. Positive control treatment with 4-nitroquinoline oxide (1X10E-5 M) produced the expected high increase in UDS (42.7 times that of solvent control).

/HUMAN EXPOSURE STUDIES/ Floxuridine should be used with extreme caution in patients who have previously received high-dose pelvic irradiation therapy or alkylating agents and in patients with impaired liver or kidney function. Floxuridine is contraindicated in patients who are in a poor nutritional state, have depressed bone marrow function (generally a leukocyte count of 5000/cu m or less and/or a platelet count of 100,000/cu m or less), or have potentially serious infections because these patients are more likely to develop serious toxicity than are patients in relatively good condition. Although severe toxicity is more likely in poor-risk patients, fatalities occasionally may occur even in patients in relatively good condition.

/SIGNS AND SYMPTOMS/ Floxuridine is a highly toxic drug with a very low therapeutic index; a therapeutic response is not likely to occur without some evidence of toxicity. The drug can produce severe hematologic toxicity, GI hemorrhage, and even death despite careful selection of patients and adjustment of dosage.

/SIGNS AND SYMPTOMS/ The expected manifestations of floxuridine overdosage include nausea, vomiting, diarrhea, GI ulceration and bleeding, and bone marrow depression (i.e., thrombocytopenia, leukopenia, and agranulocytosis).

/CASE REPORTS/ Two patients ... suffered gastrointestinal toxicity after receiving chemotherapy for unresectable lesions in the liver that metastasized from colonic carcinoma. One patient had severe lieitis caused by intravenous administration of 5-fluorouracil; the other had severe duodenitis caused by infusion of 5-floxuridine into the hepatic artery by an implanted pump. The type of toxicity that occurred was directly related to the route of administraton of these chemotherapeutic agents. Cessation of the chemotherapy led to a dramatic clinical response in these patients.

For more Human Toxicity Excerpts (Complete) data for FLOXURIDINE (6 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Floxuridine

DILI Positive

Intra-arterial

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ To investigate the etiology of floxuridine associated sclerosing cholangitis, portal vein catheters were placed in mixed-breed hounds (N= 4) and connected to an implanted infusion pump system. Floxuridine 0.3 mg/kg/day was infused for 49 to 77 days each, as a continuous infusion. Cholangiograms were performed before and after infusion, and weekly liver function tests were obtained. The results were compared to dogs (N= 6) that received hepatic arterial floxuridine 0.3 mg/kg/day X 30 days, and dogs (N= 5) that received hepatic arterial saline for 100 days. Elevation in the serum glutamic pyruvic transaminase and alkaline phosphatase, indistinguishable from the hepatic arterial group, was seen in all four dogs with portal vein infusion. Maximum bilirubin levels ranged from 0.6 to 3.0 (mean 1.7), compared to a range of 6.4 to 28 (mean 13.4) for the hepatic arterial dogs. Cholangiograms demonstrated hepatic volume loss consistent with hepatocellular injury, but no biliary sclerosis. These data suggest that sclerosing cholangitis resulting from intra-arterial infusion of floxuridine is unlikely to be due to metabolites of the drug excreted in the bile, but due to direct toxicity to the biliary tree.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ A total of 364 White Leghorn embryos were injected via the yolk sac during the third day of incubation. Uninjected and saline injected eggs served as controls. Dosages used were 0.024, 0.026, 0.028, 0.03, or 0.036 ug/egg at a concentration of 2X10(-4) g fluorodeoxyuridine/L of Howard's saline. On the tenth day of incubation the embryos were inspected for gross defects and then fixed, stained and cleared for skeletal study. All of the doses were teratogenic except the largest dose which was lethal. The most common skeletal defects were observed in vertebrae and limbs. Defects were also noted in the pelvis and mandible. Frequently, the limbs of treated embryos featured prominent hematomas. A second group of embryos were treated on the third day of incubation with 0.026 up of fluorodeoxyuridine and prepared for light and scanning electron microscopy on the fourth to the ninth days. There were early indications of hematomas in the limb buds and the frontal region of the head on the fourth day. On the fifth day definitive hematomas were observed int he limbs, frontal region, and in the lumbo-sacral region. Scanning electron micrographs revealed blood-filled blisters on the surface of the limb buds.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Floxuridine has been shown to be teratogenic in the chick embryo, mouse (at doses of 2.5-100 mg/kg), and rat (at doses of 75-150 mg/kg); malformations observed in offspring included cleft palates, skeletal defects, and deformed appendages, paws, and tails. Floxuridine dosages resulting in teratogenic effects in animal studies were 4.2-125 times the recommended human therapeutic dose.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Animal studies have not been conducted to date to evaluate the effects of floxuridine on fertility in males or females. However, fluorouracil, to which floxuridine is metabolized following intra-arterial administration, has been shown to induce chromosomal aberrations and changes in chromosome organization of spermatogonia in rats at intraperitoneal doses of 125 or 250 mg/kg. Fluorouracil also caused inhibition of spermatogonial differentiation, resulting in transient infertilty.

For more Non-Human Toxicity Excerpts (Complete) data for FLOXURIDINE (6 total), please visit the HSDB record page.

/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/

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl floxuridine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Floxuridine is an anti-metabolite or a pyrimidine analog that works by disrupting the process S-phase of cell division, selectively targeting rapidly dividing cells. Due to the structural similarities, antimetabolites act as pyrimidine-like molecules and prevent normal pyrimidines from being incorporated into DNA. After successful biotransformation, floxuridine is converted into an active component, flurouracil, which blocks the enzyme which converts cytosine nucleosides into the deoxy derivative. Flurouracil also physically prevents the incorporation of thymidine nucleotides into the DNA strand by taking their place, further preventing DNA synthesis.

Floxuridine rapidly undergoes catabolism to form 5-fluorouracil, which is the active component of the drug. 5-Fluorouracil primarily works by interfering with DNA synthesis; however, it may also inhibit the formation of fraudulent RNA via physical incorporation into the RNA. It is also an inhibitor of riboside phophorylase, preventing the utilization of pre-formed uracil in RNA synthesis. Floxuridine can also form 5-fluoro-2'-deoxyuridine-5'-phosphate (FUDR-MP), which is the monophosphate of floxuridine that inhibits thymidylate synthetase that plays a role in the methylation of deoxyuridylic acid to thymidylic acid during DNA synthesis. FUDR-MP thus interferes with DNA synthesis.

Floxuridine is an antimetabolite. The monophosphate of the drug, 5-fluoro-2'-deoxyuridine-5'-phosphate (FUDR-MP), inhibits thymidylate synthetase, thus inhibiting methylation of deoxyuridylic acid to thymidylic acid and thereby interfering with the synthesis of DNA. Following administration of a single dose of floxuridine, the drug is catabolized to fluorouracil and produces the same antimetabolic effects as the latter drug. In addition to interfering with DNA synthesis, metabolites of fluorouracil become incorporated to a small extent into RNA, producing a fraudulent RNA. Fluorouracil also inhibits utilization of preformed uracil in RNA synthesis by blocking uracil riboside phosphorylase.

Floxuridine is an antimetabolite of the pyrimidine analog type. Floxuridine is considered to be cell cycle-specific for the S-phase of cell division. Activity occurs as the result of activation in the tissue, and includes inhibition of DNA and, as a result of action of the fluorouracil metabolite, RNA synthesis.

Fluorouracil requires enzymatic conversion to the nucleotide in order to exert its cytotoxic activity. Several routes are available for the formation of the 5'-monophosphate nucleotide in animal cells. Fluorouracil may be converted to fluorouridine by uridine phosphorylase and then to 5'-monophosphate nucleotide by uridine kinase or it may react directly with 5-phosphoribosyl- 1 -pyrophosphate, catalyzed by the enzyme orotate phosphoribosyl transferase, to form 5'-monophosphate nucleotide. Fluorouracil may also be converted directly to floxuridine by the enzyme thymidine phosphorylase. Many metabolic pathways are available to 5'-monophosphate nucleotide, including incorporation into RNA. A reaction sequence crucial for antineoplastic activity involves reduction of the diphosphate nucleotide by the enzyme ribonucleotide diphosphate reductase to the deoxynucleotide level and the eventual formation of 5-fluoro-2'-deoxyuridine-5'-phosphate. This complex metabolic pathway for the generation of the actual growth inhibitor, 5-fluoro-2'-deoxyuridine-5'-phosphate, may be bypassed through use of the deoxyribonucleoside of fluorouracil--floxuridine--which is converted directly to 5-fluoro-2'-deoxyuridine-5'-phosphate by thymidine kinase. However, floxuridine is a good substrate for both thymidine and uridine phosphorylases. and it can also be degraded to fluorouracil.

Hepatic.

Biotransformation /is/ hepatic and in tissues, extensive, to the monophosphate derivative and fluorouracil; after continuous intra-arterial infusion, conversion to the monophosphate derivative is enhanced; largely converted to fluorouracil after rapid intravenous or intra-arterial injection.

Following infusion of small doses of floxuridine, most of the drug appears to be anabolized to FUDR-MP, the active metabolite of the drug. When single doses are administered rapidly, floxuridine is apparently rapidly catabolized to fluorouracil.

Floxuridine and fluorouracil are metabolized in the liver. Metabolic degradation of floxuridine is less when the drug is given by continuous infusion than when given by single injections. The drug is excreted intact and as urea, fluorouracil, a-fluoro-ß-ureidopropionic acid, dihydrofluorouracil, alpha-fluoro-beta-guanidopropionic acid, and alpha-fluoro-beta-alanine in the urine and as respiratory carbon dioxide.

Metabolic degradation occurs, particularly in the liver. Floxuridine is converted by thymidine or deoxyuridine phosphorylases into 5-fluorouracil. 5-Fluorouracil is inactivated by reduction of the pyrimidine ring; this reaction is carried out by dihydrouracil dehydrogenase, which is found in liver, intestinal mucosa, and other tissues. Inherited deficiency of this enzyme leads to greatly increased sensitivity to the drug. The product of this reaction, 5-fluoro-5,6-dihydrouracil is ultimately degraded to alpha-fluoro-beta-alanine ... .

039LU44I5M

FLOXURIDINE

Established Pharmacologic Class [EPC] - Antimetabolite

Chemical Structure [CS] - Deoxyuridine

Floxuridine is an Antimetabolite.

FLOXURIDINE

Floxuridine can be excreted as unchanged drug, urea, fluorouracil, a-fluoro-bureidopropionic acid, dihydrofluorouracil, a-fluoro-b-guanidopropionic acid and a-fluoro-b-alanine via the kidneys. Floxuridine may also be excreted as respiratory carbon dioxide.

... Floxuridine /is/ ... administered parenterally, since absorption after ingestion ... is unpredictable and incomplete.

It is not known whether floxuridine is distributed into milk.

Some /Floxuridine/ crosses the blood-brain barrier; active metabolites are localized intracellularly.

Elimination /is/ respiratory (as carbon dioxide), about 60%. Renal /elimination accounts for/ 10 to 13% (as unchanged drug and metabolites).

THERAP CAT: Antiviral; antineoplastic

MEDICATION

...Powder, 500 mg in 5-ml containers.

HOFFER ET AL, J AM CHEM SOC 81, 4112 (1959); HEIDELBERGER, DUSCHINSKY, US PATENT 2,885,396 (1959); DUSCHINSKY ET AL, US PATENT 2,970,139 (1961); HOFFER, US PATENTS 2,949,451; 3,041,335 (1960, 1962 BOTH TO HOFFMANN-LA ROCHE).