Colchicine

Teratogens

-> NIOSH Emergency Response Categories

Pale yellow scales or powder; pale yellow needles when crystallized from ethyl acetate

Yellow plates from water + 1/2 mol of water of crystallization; yellow crystals from benzene

greater than or equal to 100 mg/mL at 70 °F (NTP, 1992)

1 g dissolves in 22 mL water, 220 mL ether, 100 mL benzene; freely sol in alcohol or chloroform; practically insoluble in petroleum ether

SOL IN METHANOL; SLIGHTLY SOL IN CARBON TETRACHLORIDE

At 25 °C, 4.5 g/100 g water

Breast Feeding; Lactation; Milk, Human; Antigout Agents; Antimitotic Agents; Gout Suppressants

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Pharmaceuticals

Danger

H300: Fatal 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)

Danger

H300+H330 (25.9%): Fatal if swallowed or if inhaled [Danger Acute toxicity, oral; acute toxicity, inhalation]

P203, P260, P262, P264, P264+P265, P270, P271, P280, P284, P301+P316, P302+P352, P304+P340, P305+P354+P338, P316, P317, P318, P320, P321, P330, P361+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Hazard Traits - Developmental Toxicity; Genotoxicity; Reproductive Toxicity

Status: Active Update: 29-09-2010 https://echa.europa.eu/registration-dossier/-/registered-dossier/1277

Colchicine: Does not have an individual approval but may be used under an appropriate group standard

The New Jersey Worker and Community Right to Know Act requires public and private employers to provide information about hazardous substances at their workplaces. (N.J.S.A. 34:5A-1 et. seq.)

IMAP assessments - Acetamide, N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl)-, (S)-: Human health tier I assessment

- Indoor Air: Colchicine can be released into indoor air as fine particles or liquid spray (aerosol).

It is classified as super toxic. Probable oral lethal dose in humans is less than 5 mg/kg, i.e. less than 7 drops for a 70 kg (150 lb.) person. Death results from respiratory arrest. The fatal dose varies considerably; as little as 7 mg of colchicine has proved fatal. (EPA, 1998)

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

For drugs, solid, n.o.s., avoid breathing dusts and fumes from burning material. Keep upwind. Wear boots, protective gloves, and goggles.

- Colchicine is non-combustible.

If a tank, rail car, or tank truck is involved in a fire, isolate it for 0.5 miles (800 m) in all directions; also consider initial evacuation for 0.5 miles (800 m) in all directions.

For large fires, use water spray, fog, or regular foam. Move containers from the fire area if it is possible to do so without risk to personnel. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. For fire involving tanks or car/trailer loads, fight the fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after the fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tanks. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from the area and let the fire burn. Run-off from fire control or dilution water may be corrosive and/or toxic, and it may cause pollution. If the situation allows, control and properly dispose of run-off (effluent).

For fire involving tanks or car/trailer loads, fight the fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after the fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tanks. Always stay away from tanks engulfed in fire.

Run-off from fire control or dilution water may be corrosive and/or toxic, and it may cause pollution. If the situation allows, control and properly dispose of run-off (effluent).

For more Fire Fighting Procedures (Complete) data for COLCHICINE (6 total), please visit the HSDB record page.

Wipe up spillage or collect spillage using a high efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labelled container for disposal. Wash spill site.

Do not touch or walk through the spilled agent if at all possible. However, if you must, personnel should wear the appropriate personal protective equipment (PPE) during environmental decontamination. ... Keep combustibles (e.g., wood, paper, and oil) away from the spilled agent. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact the spilled agent. Do not direct water at the spill or the source of the leak. Stop the leak if it is possible to do so without risk to personnel, and turn leaking containers so that gas rather than liquid escapes. Prevent entry into waterways, sewers, basements, or confined areas. Isolate the area until gas has dispersed. Ventilate the area.

Precautions for drugs, solid, n.o.s., include the following. Avoid breathing dusts, and fumes from burning materials. Keep upwind. Avoid bodily contact with the material. Wear full protective clothing. Wash away any material which may have contacted the body with copious amounts of water or soap and water. (EPA, 1998)

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

SRP: The scientific literature for the use of contact lenses by industrial workers is inconsistent. The benefits or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.

Information is inconclusive about the carcinogenicity, developmental toxicity, or reproductive toxicity from chronic or repeated exposure to colchicine. Effects of chronic exposure to colchicine are mainly known from its use as a drug in human medicine. In these circumstances gastrointestinal symptoms are likely to cause discontinuation of the use of the drug, long before any other symptoms develop. Bone marrow depression with a condition marked by fever and other symptoms (agranulocytosis), persistent decrease in the number of blood platelets (thrombocytopenia), reduced white blood cell count (leukopenia), and anemia characterized by defective function of the blood-forming organs (aplastic anemia) may occur with prolonged colchicine administration. Loss of body and scalp hair (alopecia), rashes, blister-like inflammation of the skin (vesicular dermatitis), degeneration of certain nerves (peripheral neuritis or neuropathy), a break down of muscle tissue at the cellular level (myopathy), the absences of urine excretion (anuria), kidney (renal) damage, blood in the urine (hematuria), and one case of patches of purplish discoloration of the skin and mucous membranes (purpura) have also been reported with prolonged administration of colchicine.

0.082 [mg/m3]

0.90 [mg/m3]

1.9 [mg/m3]

For emergency situations, wear a positive pressure, pressure-demand, full facepiece self-contained breathing apparatus (SCBA) or pressure- demand supplied air respirator with escape SCBA and a fully-encapsulating, chemical resistant suit. (EPA, 1998)

First Responders should use a NIOSH-certified Chemical, Biological, Radiological, Nuclear (CBRN) Self Contained Breathing Apparatus (SCBA) with a Level A protective suit when entering an area with an unknown contaminant or when entering an area where the concentration of the contaminant is unknown. Level A protection should be used until monitoring results confirm the contaminant and the concentration of the contaminant. NOTE: Safe use of protective clothing and equipment requires specific skills developed through training and experience. [Table#4370]

GENERAL INFORMATION

Colchicine is distributed into human milk. In a limited number of nursing women receiving long-term colchicine therapy at dosages of 1-1.5 mg daily, peak concentrations of the drug in milk were similar to serum concentrations and ranged from 1.9-8.6 ng/mL. Higher concentrations of the drug in milk (31, 24-27, or 10 ng/mL at 2, 4, or 7 hours, respectively, after a dose) have been reported in the absence of concurrent serum concentration data in a nursing woman receiving colchicine 1 mg daily.

Colchicine has been shown to induce reversible malabsorption of vitamin B12, apparently by altering the function of ileal mucosa.

Results of animal studies have suggested that colchicine may enhance response to sympathomimetic agents and CNS depressants.

(1) Renal failure, either pre-existing or induced by a nephrotoxic drug, increases the risk of adverse effects in patients taking colchicine; (2) Combining colchicines with a macrolide (except for spiramycin) carries a risk of life-threatening pancytopenia; (3) Ciclosporin co-administration can aggravate the neuromuscular adverse effects of colchicine; (4) Combining colchicine with lipid-lowering drugs (statins and fibrates) can cause myopathy; (5) Several mechanisms have been implicated: competition for cytochrome P450 or P-glycoprotein, additive adverse effects (especially on muscle), and colchicine accumulation due to a reduction in its renal excretion; (6) Patients with gout should use colchicine only after failure of symptomatic treatment: ice application, paracetamol, and possibly ibuprofen, a nonsteroidal antiinflammatory drug with well-documented adverse effects; (7) If colchicine is nevertheless used, it should be at the minimum effective dose. Close clinical monitoring is required in order to detect early signs of adverse effects, especially diarrhea, the earliest sign in patients with renal failure and in the elderly.

Colchicine and 3-hydroxy-3-methy-glutaryl coenzyme A (HMG-CoA) reductase inhibitors are well known to cause myopathy. Myotoxicity is dose-dependent in both drugs; therefore, the onset of symptoms usually takes months or years. We report the case of a patient with chronic renal failure who had been taking simvastatin for 2 years and developed acute weakness 2 weeks after the start of treatment with colchicines for recurrent gout. The electromyography and elevated muscle enzymes indicated that his symptoms were caused by myopathy. When this patient stopped taking both drugs, his weakness resolved rapidly. Acute myopathy induced by combination therapy with colchicines and simvastatin is rare. In patients with chronic renal failure, co-administration of colchicine with simvastatin may accelerate the onset of myopathy because CYP3A4 (part of cytochrome P450) is crucial in the breakdown of both drugs. When adding colchicine to a medication regimen that includes a HMG-CoA reductase inhibitor for patients with renal insufficiency, drugs that are metabolized outside the CYP3A4 system (e.g., fluvastatin and pravastatin) should be selected instead.

For more Interactions (Complete) data for COLCHICINE (13 total), please visit the HSDB record page.

Chronic therapy with colchicine is uncommonly associated with serum aminotransferase or alkaline phosphatase elevations and has, indeed, been used off label as therapy of liver diseases, including alcoholic hepatitis and primary biliary cirrhosis. Despite decades of wide spread use, there have been no published cases of idiosyncratic liver disease attributed to colchicine use. Interestingly, liver biopsies done in patients receiving colchicine often show scattered mitotic figures in hepatocytes (ring mitoses) without accompanying liver cell injury.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1,900(SRC), determined from a log Kow of 1.03(2) and a structure estimation method(3), indicates that colchicine is expected to have low mobility in soil(SRC). Volatilization of colchicine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.8X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Colchicine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.2X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Biodegradation data in soil were not available(SRC, 2009).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1,900(SRC), determined from a log Kow of 1.03(2) and a structure estimation method(3), indicates that colchicine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 1.8X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 2.2(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2009).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), colchicine, which has an estimated vapor pressure of 3.2X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase colchicine may be removed from the air by wet or dry deposition(SRC). Colchicine contains chromophores that absorb at wavelengths >290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC).

The most common adverse reactions are related to the gastrointestinal tract. Diarrhea is the most commonly reported symptom (23%), followed by vomiting (17%) and nausea (4% to 17%). Central nervous system symptoms, such as fatigue and headache, and endocrine and metabolic conditions, such as gout and pharyngolaryngeal pain, have been reported.

Colchicine can be absorbed into the body by ingestion, inhalation, or eye contact. Colchicine can also be injected through the skin or administered intravenously. It is unknown whether colchicine can be absorbed through intact skin.

Colchicine is rapidly absorbed after oral administration, probably from the jejunum and ileum. However, the rate and extent of absorption are variable, depending on the tablet dissolution rate; variability in gastric emptying, intestinal motility, and pH at the absorption site; and the extent to which colchicine is bound to microtubules in gastrointestinal mucosal cells.

EXPERIMENTAL: Colchicine is distributed into human milk. In a limited number of nursing women receiving long-term colchicine therapy at dosages of 1-1.5 mg daily, peak concentrations of the drug in milk were similar to serum concentrations and ranged from 1.9-8.6 ng/mL. Higher concentrations of the drug in milk (31, 24-27, or 10 ng/mL at 2, 4, or 7 hours, respectively, after a dose) have been reported in the absence of concurrent serum concentration data in a nursing woman receiving colchicine 1 mg daily.

IDENTIFICATION: Colchicine is an antigout preparations. Colchicine is available as tablets and, in some countries, as injectable solutions. Colchicine is an alkaloid of Colchicum autumnale (autumn crocus, meadow saffron). Colchicum is also present in Gloriosa superba. Colchicine is a pale yellow odorless powder or scales. It darkens on exposure to light. Colchicine is used for acute gout attacks to reduce pain and inflammation. It may be used on long-term basis to prevent or reduce the frequency of attacks. Colchicine is used on long-term basis to prevent fever and recurrent polyserositis. Colchicine is effective in preventing the amyloidosis in this condition. Colchicine has been showed to be effective in the treatment of articular, cutaneous and mucosal symptoms. Colchicine has been used in the treatment of scleroderma and sarcoidosis. HUMAN EXPOSURE: Main risks and target organs: Colchicine exerts a multiorgan toxicity. The main toxic effects are related to the effects of colchicine on cellular division and account for diarrhea, bone marrow depression, alopecia. Other acute effects are hypovolemia, shock, and coagulation disturbances, which may lead to death. Summary of clinical effects: Toxic manifestations appear after a delay of 2 to 12 hours following ingestion or parenteral administration. Symptomatology progresses in three stages: Stage I (Day 1 to 3) gastrointestinal and circulatory phase: Severe gastrointestinal irritation: Nausea, vomiting, abdominal cramps, severe diarrhea. Dehydration, hypovolemia, shock. Cardiogenic shock may occur and may result in death within the first 72 hours. Hypoventilation, acute respiratory distress syndrome. Stage II (Day 3 to 10) bone marrow aplasia phase: Bone marrow aplasia with agranulocytosis. Coagulation disorders with diffuse hemorrhages. Rhabdomyolysis, polyneuritis, myopathy, acute renal failure and infections. Stage III: (After 10 day) recovery phase: Alopecia. Routes of entry: Oral: Oral absorption is the most frequent cause of intoxication. Parenteral: Intoxications after parenteral administration are rare, however, the toxic dose appears to be lower than the oral toxic dose. A fatal bone marrow aplasia in a 70 year-old man after 10 mg intravenous colchicine over 5 days. Intoxication with multisystemic reactions after instillation of colchicine into the penile urethra for treatment of condyloma acuminata. Absorption by route of exposure: Oral: Rapidly absorbed from the gastro-intestinal tract. Peak plasma concentration is reached 0.5 to 2 hours after ingestion. Half time of absorption is 15 minutes. Absorption may be modified by pH, gastric contents, intestinal motility. Colchicine is not totally absorbed. There is an important hepatic first pass effect. Colchicine distributes in a space larger than that of the body. In severe renal or liver diseases the volume of distribution is smaller. Colchicine accumulates in kidney, liver, spleen, gastro-intestinal wall and leucocytes and is apparently excluded in heart, brain, skeletal muscle. Colchicine crosses the placenta and has also been found in maternal milk. Biological half-life by route of exposure: Parenteral: After a single 2 mg intravenous dose the average plasma half-life is 20 minutes. Plasma half-life is increased in severe renal disease (40 min) and decreased in severe hepatic disease (9 min). Oral: After oral administration plasma concentrations reach a peak within 0.5 to 2 hours and afterwards decrease rapidly within 2 hours. The plasma half-life is 60 minutes. Colchicine may remain in tissues for as long as 10 days. Metabolism: Colchicine undergoes some hepatic metabolism. Colchicine is partially deacetylated in the liver. Large amounts of colchicine and of its metabolites undergo enterohepatic circulation. This may explain the occurrence of a second plasma peak concentration observed 5 to 6 hours after ingestion. Elimination by route of exposure: Colchicine is excreted unchanged (10 to 20 percent) or as metabolites. Oral: Urinary excretion amount to 16 to 47% of an administered dose. 50 to 70% of colchicine is excreted unchanged and 30 to 50% as metabolites. 20% of the dose administered is excreted in urine in the first 24 hours and 27.5% in the first 48 hours. Colchicine is detected in urine up to 7 to 10 days after ingestion. Urinary excretion is increased in patients with impaired hepatic function. Bile: 10 to 25% of colchicine is excreted in the bile. Feces: Large amounts of the drug are excreted in the feces. Breast Milk: Colchicine may be eliminated in breast milk. Intravenous: Feces: After intravenous administration 10 to 56% is excreted in the feces within the first 48 hours. Breast Milk: Colchicine may be eliminated in breast milk. Mode of action: Colchicine binds to tubulin and this prevents its polymerization into microtubules. The binding is reversible and the half-life of the colchicine-tubulin complex is 36 hours. Colchicine impairs the different cellular functions of the microtubule: separation of chromosome pairs during mitosis (because colchicine arrests mitosis in metaphase), ameboid movements, phagocytosis. Mitosis blockade accounts for diarrhoea, bone marrow depression and alopecia. Colchicine may have a direct toxic effect on muscle, peripheral nervous system and liver. Inhibition of cellular function does not, however, account for all the organ failures seen in severe overdose. Pharmacodynamics: Gout inflammation is initiated by urate crystals within tissues. The crystals are ingested by neutrophils but this leads to the release of enzymes and the destruction of the cells. Chemotactic factors are released and attract more neutrophils. Colchicine may act by preventing phagocytosis, the release of chemotactic factors and the response of neutrophils. Colchicine has other properties such as antipyretic effects, respiratory depression, vasoconstriction and hypertension. Adults: Oral: The severity and the mortality rate of the poisoning is directly related to the dose ingested. Intravenous: A fatal bone marrow aplasia in a 70-year-old patient is reported. The enhanced toxicity of intravenous colchicine is probably due to the higher bioavailability of colchicine after parenteral administration. Teratogenicity: Colchicine is contraindicated in pregnancy as Down's syndrome and spontaneous abortion have been reported. Colchicine should be discontinued three months prior to conception. Interactions: A case of acute cyclosporin nephrotoxicity induced by colchicine administration has been reported. Colchicine may interfere with cyclosporin pharmacokinetics by increasing cyclosporin plasma levels either by enhancing cyclosporin absorption or by reducing its hepatic metabolism. Main adverse effects: Gastrointestinal symptoms are a common complication of chronic colchicine therapy. Fatal outcomes have been reported after intravenous colchicine therapy. Gastrointestinal: vomiting, diarrhoea, abdominal discomfort, paralytic ileus, malabsorption syndrome with steatorrhea. Hematological: Bone marrow depression with agranulocytosis, acute myelomonocytic leukaemia, multiple myeloma, thrombocytopenia. Neurological: Peripheral neuritis, myopathy and rhabdomyolysis. Dermatological: Allergic reactions are rare urticaria; oedema may be seen. Alopecia has been reported after chronic treatment. Reproductive system: A reversible, complete azoospermia has been reported. Metabolic: Colchicine is capable of producing a reversible impairment of vitamin B12 absorption. Porphyria cutanea tarda has been reported. Others: Hyperglycemia has been reported in a 58-year-old woman who ingested colchicine and developed transient diabetes mellitus has been reported. Hyperlipemia: A transient hyperlipemia has been reported. Hyperuricemia: A transient hyperuricemia has also been noted. Hyperthermia-fever: Occurrence of fever may be relate to an infectious complication, especially during the stage of aplasia. Special risks: Pregnancy: Two cases of Down's syndrome babies have been reported. The obstetric histories of 36 women with familial Mediterranean fever on long-term colchicine treatment between 3 and 12 years have been reported. Seven of 28 pregnancies ended in miscarriage. Thirteen women had periods of infertility. All 16 infants born to mothers who had taken colchicine during pregnancy were healthy. The authors do not advise discontinuation of colchicine before planned pregnancy but recommend amniocentesis for karyotyping and reassurance. Breast-feeding: As colchicine is eliminated in the breast milk breast-feeding should be avoided.

The precise dose of colchicine that results in significant toxicity is unknown. Toxicity can occur after ingesting a dose as low as 7 mg over 4 days, while other patients have survived after taking doses exceeding 60 mg. In one review involving 150 patients who experienced a colchicine overdose, ingesting doses exceeding 0.8 mg/kg resulted in death.

Colchicine inhibits microtubule assembly in various cells, including leukocytes, probably by binding to and interfering with polymerization of the microtubule subunit tubulin. Although some studies have found that this action probably does not contribute significantly to colchicine's antigout action, a recent in vitro study has shown that it may be at least partially involved.

- Eye contact with liquid colchicine may produce clouding of the cornea that clears in a few weeks.

- Gastrointestinal phase: Nausea; loss of appetite (anorexia); abdominal pain; vomiting (emesis); profuse, watery, and bloody diarrhea; joint pain; generalized weakness; fever; rashes; and hypovolemic shock.

- See Signs/Symptoms Ingestion Exposure.

- .

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical.[Available from, as of September 30, 2009: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=64-86-8]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of colchicine can be estimated to be 1,900(SRC). According to a classification scheme(2), this estimated Koc value suggests that colchicine is expected to have low mobility in soil.

Colchicine is an alkaloid of the meadow saffron, Colchicum autumnale. The plant has been used in the treatment of articular disorders since the sixth century(1).

Colchicine, an alkaloid, is found in Colchicum autumnale (common names: Meadow Saffron, Autumn Crocus), as well as in Colchicum luteum, Merendera persica, Androcymbium gramineum,Gloriosa superba, Littonia modesta.

From Colchicum autumnale by extraction and subsequent crystallization.

COLCHICUM AUTUMNALE (MEADOW SAFFRON, AUTUMN CROCUS) IS LOCALLY ABUNDANT IN MEADOWS THROUGHOUT MOST OF EUROPE, & HAS BECOME NATURALIZED IN PARTS OF AMERICA. ALL PARTS OF /COLCHICUM AUTUMNALE/ ... CONTAIN THE ALKALOIDS COLCHICINE & COLCHICEINE, OF WHICH THE FORMER IS MORE TOXIC. BOTH ALKALOIDS WITHSTAND STORAGE, DRYING, AND BOILING.

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

Colchicine is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 10 or 10,000 lbs. Extremely hazardous substances that are solids are subject to either of two threshold planning quantities ... The lower quantity applies only if the solid exists in powdered form and has a particle size less than 100 microns; or is handled in solution or in molten form; or meets the criteria for a National Fire Protection Association (NFPA) rating of 2, 3 or 4 for reactivity. If the solid does not meet any of these criteria, it is subject to the upper ... threshold planning quantity ... .

M04AC01

M - Musculo-skeletal system

QM - Musculo-skeletal system

Colchicine ameliorates the symptoms of gout and Familial Mediterranean fever. It possesses anti-inflammatory, anti-fibrotic, and cardiovascular protective effects. Colchicine was shown to exhibit anticancer properties, such as the inhibition of cancer cell migration and angiogenesis. Colchicine has a narrow therapeutic window.

The exact mechanism of action of colchicine has not been fully established; however, colchicine likely interferes with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β, an inflammatory mediator. Colchicine also attenuates neutrophil adhesion and recruitment, as well as superoxide production. Clinical data demonstrate that colchicine reduces high-sensitivity C- reactive protein (hs-CRP). Colchicine is an anti-mitotic drug that disrupts cytoskeletal functions by inhibiting β-tubulin polymerization into microtubules. Consequently, it prevents the activation, degranulation, and migration of neutrophils. This pharmacological action is thought to be related to colchicine ameliorating gout symptoms and preventing major cardiovascular events. Colchicine blocks microtubule growth at low concentrations and causes the depolymerization of microtubules at high concentrations.

... HUVEC cells were exposed to various concentrations of colchicine and were harvested at different time points. Ribonucleic acid was extracted, amplified, reverse transcribed and hybridized to complementary deoxyribonucleic acid microarrrays containing more than 40,000 probes to human expressed sequence tags. This approach enabled us to have a global look at the transcriptional response induced by colchicine treatment. Colchicine changed the expression of many genes in HUVEC cells following exposure to a concentration of 100 ng/ml or higher. Following short exposure (30 or 120 min), colchicine affected genes known to be involved in the cell cycle and its regulation. However, change in expression of genes involved in neutrophil migration or other inflammatory processes were observed mainly after 12 to 24 hr. The anti-inflammatory effect of colchicine may be mediated not only through direct interaction with microtubules but also through changes at the transcriptional level. This latter effect apparently requires a higher concentration and a longer time to occur.

Colchicine, long used to treat gout, arrests microtubule assembly and inhibits many cellular functions. At micromolar concentrations, it suppresses monosodium urate crystal-induced NACHT-LRR-PYD-containing protein-3 (NALP3) inflammasome-driven caspase-1 activation, IL-1beta processing and release, and L-selectin expression on neutrophils. At nanomolar concentrations, colchicine blocks the release of a crystal-derived chemotactic factor from neutrophil lysosomes, blocks neutrophil adhesion to endothelium by modulating the distribution of adhesion molecules on the endothelial cells, and inhibits monosodium urate crystal-induced production of superoxide anions from neutrophils. Cyto-chrome P450 3A4, the multidrug transporter P-glycoprotein, and the drugs that bind these proteins influence its pharmacokinetics and pharmacodynamics. Trial evidence supports its efficacy in acute gout and in preventing gout flares, but it has narrow therapeutic index, and overdosage is associated with gastrointestinal, hepatic, renal, neuromuscular, and cerebral toxicity; bone marrow damage; and high mortality.

The actions of colchicine were examined with the two-electrode voltage-clamp technique and radioligand binding assays in mouse and human 5-hydroxytryptamine(3A) receptors (5-HT(3A)Rs) expressed in Xenopus laevis oocytes. Colchicine inhibited 5-hydroxytryptamine (5-HT)-evoked currents in oocytes expressing mouse 5-HT(3A)Rs, with an IC(50) of 59.5 +/- 3 uM. In contrast to the mouse receptor, coapplication of colchicine with 5-HT (<1 uM) strongly enhanced 5-HT-evoked currents in oocytes expressing human 5-HT(3A)Rs. Colchicine applied alone did not induce a detectable current. In the presence of 0.5 microM 5-HT, the potentiation was concentration-dependent and reached the maximum (approximately 100%) when 750 microM colchicine was applied. However, colchicine-dependent inhibition can be observed at 5-HT concentrations > 1 uM. In oocyte membranes expressing mouse or human receptors, binding studies with colchicine (25 nM-1 mM) revealed no displacement of 1-methyl-N-((1R,3r,5S)-9-methyl-9 azabicyclo [3.3.1]nonan-3yl)-1H-indazole-3 carboxamide ([(3)H]BRL-43694), suggesting that actions of colchicine do not occur at the ligand binding domain. Functional effects of colchicine on both receptors occurred in the absence of preincubation and after cold temperature incubation, suggesting that the microtubule-depolymerizing effects of colchicine play no role in modulation of receptor function. Studies with interspecies chimeric receptors demonstrated that the distal one third of the N terminus is responsible for the bidirectional modulation by colchicine. Collectively, these results suggest that colchicine modulates receptor function through loops C and/or F through a gating mechanism.

Colchicine exerts a variety of pharmacological effects, but how these occur or how they relate to its activity in gout is not well understood. It has antimitotic effects, arresting cell division in GI by interfering with microtubule and spindle formation (an effect shared with vinca alkaloids). This effect is greatest on cells with rapid turnover (e.g., neutrophils and GI epithelium). Although somewhat controversial, colchicine may alter neutrophil motility in ex vivo assays. Colchicine also renders cell membranes more rigid and decreases the secretion of chemotactic factors by activated neutrophils.

For more Mechanism of Action (Complete) data for COLCHICINE (8 total), please visit the HSDB record page.

After several doses of 0.6 mg twice daily, the average elimination half-life of colchicine ranges from 26.6 to 31.2 hours. Another study reported the elimination half-life ranging to be 20 to 40 hours.

Following IV administration of a single therapeutic dose (as of August 2008, IV preparations are no longer commercially available in the US), colchicine is rapidly removed from the plasma; plasma half-life is about 20 minutes. The drug has a half-life of about 60 hours in leukocytes.

The elimination half life is variable, ranging from 4.4 hours in normal patients to 30 hours or more in elderly patients. A therapeutic dose produced a half life of 18.8 hours in patients with renal dysfunction.

After a single 2 mg intravenous dose the average plasma half life is 20 minutes. Plasma half-life is increased in severe renal disease (40 min) and decreased in severe hepatic disease (9 min).

Colchicine is metabolized in the liver. It undergoes CYP3A4-mediated demethylation into major metabolites, 2-O-demethylcolchicine and 3-O-demethylcolchicine. It also forms one minor metabolite, 10-O-demethylcolchicine ([colchiceine]). Plasma levels of these metabolites are less than 5% of parent drug.

Colchicine undergoes some hepatic metabolism. Colchicine is partially deacetylated in the liver. Large amounts of colchicine and of its metabolites undergo enterohepatic circulation. This may explain the occurrence of a second plasma peak concentration observed 5 to 6 hours after ingestion.

Three novel conjugation metabolites of colchicine were identified in rat bile facilitated by enhanced on-line liquid chromatography-accurate radioisotope counting. The known 2- and 3-demethylcolchicines (DMCs) underwent O-sulfate conjugation in addition to the previously described O-glucuronidation. 2-DMC was preferably O-glucuronidated, whereas 3-DMC predominantly yielded O-sulfation conjugates, indicating phase II conjugation regiopreferences. Moreover, M1 was identified as a novel glutathione conjugate and a possible biotransformation pathway for its formation was proposed. The known 2-DMC (M6), 3-DMC (M7), 2-DMC glucuronide (M4), and novel 3-DMC sulfate (M3) were confirmed as the major metabolites. ...

Probably hepatic. Although colchicine metabolites have not been identified in humans, metabolism by mammalian hepatic microsomes has been demonstrated in vitro. Route of Elimination: In healthy volunteers (n=12) 40 - 65% of 1 mg orally administered colchicine was recovered unchanged in urine. Enterohepatic recirculation and biliary excretion are also postulated to play a role in colchicine elimination. Half Life: Elimination half-life is approximately 1 hour in healthy subjects, although a study with an extended sampling time reported mean terminal elimination half-life values of approximately 9 to 10.5 hours. Other studies have reported half-life values of approximately 2 hours in patients with alcoholic cirrhosis and approximately 2.5 hours in patients with familial Mediterranean fever.

SML2Y3J35T

COLCHICINE

Established Pharmacologic Class [EPC] - Alkaloid

Chemical Structure [CS] - Alkaloids

Colchicine is an Alkaloid.

COLCHICINE

Agents that increase uric acid excretion by the kidney (URICOSURIC AGENTS), decrease uric acid production (antihyperuricemics), or alleviate the pain and inflammation of acute attacks of gout.

Agents that interact with TUBULIN to inhibit or promote polymerization of MICROTUBULES.

Colchicine is rapidly absorbed after oral administration from the gastrointestinal tract. The bioavailability of colchicine is about 45%: one study suggests that colchicine bioavailability is highly variable, ranging from 24 to 88%. In healthy adults, the mean Cmax of 2.5 ng/mL (range 1.1 to 4.4 ng/mL) was achieved in one to two hours (range 0.5 to 3 hours) after a single dose administered under fasting conditions. In a multiple-dose study of colchicine administration at a dose of 1 mg per day, steady-state concentrations were achieved by day 8 following administration. Administration of colchicine with food does not affect the colchicine absorption rate but decreases the extent of colchicine by approximately 15%.

In a pharmacokinetic study of healthy research subjects who received 1 mg of oral colchicine, about 40% to 65% of the dose was recovered in the urine in the form of an unchanged drug. Colchicine undergoes enterohepatic recirculation and biliary excretion.

The mean apparent volume of distribution in young and healthy patients is about 5-8 L/kg. It is known to cross the placenta and distribute into the breast milk. Colchicine has been found to distribute to various tissues, mainly into the bile, liver, and kidney tissues. Smaller amounts have been detected in the heart, lungs, intestinal tissue, and stomach.

In one pharmacokinetic study involving patients who received a single oral dose of 0.6 mg colchicine, the clearance was 0.0321 ± 0.0091 mL/min in young, healthy adults and 0.0292 ± 0.0071 mL/min in adults between the ages of 60 and 70 years. Patients with end-stage renal impairment showed a 75% lower clearance of colchicine. In a pharmacokinetic study of patients with Familial Mediterranean Fever (FMF), the apparent mean clearance was calculated at 0.726 ± 0.110 L/h/kg.

The absorption of colchicine is rapid but variable. Peak plasma concentrations occur 0.5 to 2 hours after dosing. In plasma, 50% of colchicine is protein-bound. There is significant enterohepatic circulation. The exact metabolism of colchicine is unknown but seems to involve deacetylation by the liver. Only 10% to 20% is excreted in the urine, although this increases in patients with liver disease. The kidney, liver, and spleen also contain high concentrations of colchicine, but it apparently is largely excluded from heart, skeletal muscle, and brain. The plasma half-life of colchicine is approximately 9 hours, but it can be detected in leukocytes and in the urine for at least 9 days after a single intravenous dose.

... Two cases involving suicide by the ingestion of medications marketed in France /is reported/. In case 1, only heart blood was taken after body external examination. In case 2 an autopsy was performed and heart blood, urine, gastric contents and bile were taken for toxicological analysis. Colchicine was assayed in biological specimens by an HPLC-DAD method, after extraction by dichloromethane at pH 8, adding prazepam as internal standard (IS). Analyses were performed on a Symetry C-8 column. Mobile phase was a gradient of acetonitrile/pH 3.8 phosphate buffer. Colchicine is eluted at 13.1 min and the method is linear for blood, urine and bile over the range 4-1000 ng/mL. LOQ is 4 ng/mL. The concentrations of colchicine detected are: case 1: heart blood 13 ng/mL; case 2: heart blood 66 ng/mL, urine 500 ng/mL, gastric content 12 ng/mL, bile 5632 ng/mL. Our findings are in the range of lethal concentrations previously described, but there is no correlation with the amount of ingested drug. Even after massive overdose, it could be impossible to detect colchicine in blood, and as there is a widespread enterohepatic recirculation before excretion in bile and feces, bile is the target sample to analyse. We conclude in both cases that the cause of death was suicide with colchicine. It appears very important to perform an autopsy in order to obtain bile, urine, heart blood and femoral blood.

In research in plant genetics (for doubling chromosomes)

To induce chromosome doubling in plants; phytopathology.

Relieves acute attacks of gout

Therapeutic Category: Gout suppressant. Treatment of Familial Mediterranean Fever

For more Uses (Complete) data for COLCHICINE (8 total), please visit the HSDB record page.

Colchicine is a highly toxic plant hormone that is used medically in the treatment of gout and in scientific research. Colchicine stops the process of cell division (it is an antimitotic agent). Exposure to colchicine can be fatal in very small doses (e.g., 7 to 65 mg). Colchicine is derived from the meadow saffron or autumn crocus plant (Colchicum autumnale), which is locally abundant in meadows throughout most of Europe and has become naturalized in parts of North America. It can also be found in the tubers of the Glory Lily (Gloriosa superba) found primarily in Florida. It is odorless or nearly so and has a very bitter taste. It is produced in tablets, granules, and ampules of sterile solution. It has uses in the production of legitimate and illicit plant production.

Beta-lumicolchicine

Colchiceine

Colchicoside

N-deacetyl-N-formylcolchicine

For more Impurities (Complete) data for COLCHICINE (6 total), please visit the HSDB record page.

The seeds of the meadow saffron (Colchicum autumnale L.) are extracted with boiling alcohol to obtain colchicine. Because of its solubility, it can be separated from accompanying substances: the extract is evaporated and the residue mixed with water. The undissolved resins and fats are filtered off and the filtrate extracted with chloroform. After evaporation of the chloroform solution the procedure is repeated with the residue. When the purity is sufficient, the colchicine crystallizes from the concentrated chloroform solutions as a chloroform complex.

Extraction from the plant Colchicum autumnale with ethanol, followed by water treatment, filtration, extraction with petroleum ether, extraction with chloroform, concentration of the residue, and distillation

By extracting ... seed with alc. After distilling off alc, syrupy residue is diluted with water to precipitate fats and resins and filtered. Filtrate is digested with some lead carbonate, refiltered, evaporated to small vol and colchicine extracted with chloroform.

From Colchicum autumnale by extraction and subsequent crystallization. Has been synthesized.

Grades: technical; United States Pharmacopeia.

Colchineos

Colchisol

Colcin

For more Formulations/Preparations (Complete) data for COLCHICINE (7 total), please visit the HSDB record page.

Acetamide, N-[(7S)-5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl]-: ACTIVE

All parts of /Colchicum autumnale/ ... contain the alkaloids colchicine and colchiceine, of which the former is more toxic. Both alkaloids withstand storage, drying, and boiling.

Colchicum autumnale ... has been used in the treatment of articular disorders since the sixth century