Colchicine metabolism

Clarithromycin may have inhibited colchicine metabolism and caused a rise in colchicine concentration. 

Allopurinol (Zyloprim) reduces the production of uric acid, thus decreasing serum uric acid levels and the deposit of urate crystals in joints. The exact mechanism of action of colchicine is unknown, but it does reduce the inflammation associated with the deposit of urate crystals in the joints. This probably accounts for its ability to relieve the severe pain of acute gout. Colchicine has no effect on uric acid metabolism. 

Oral colchicine is absorbed rapidly from the gastrointestinal tract and metabolized extensively in the liver. 

A variety of cell lines, strains, or primary cell cultures, including human cells, may be used (e.g., Chinese hamster fibroblasts, human or other mammalian peripheral blood lymphocytes). Cell cultures are exposed to the test substance both with and without metabolic activation and at predetermined intervals after exposure, they are treated with a metaphase-arresting substance (e.g., colchicine), harvested, stained, and metaphase cells are analyzed microscopically for the presence of structural chromosome aberrations. At least three concentrations should be used. 

Pharmacokinetics Colchicine is rapidly absorbed after oral administration peak plasma concentrations occur in 0.5 to 2 hours. High colchicine concentrations are found in the kidney, liver, and spleen. It is metabolized in the liver. Excretion occurs primarily by biliary and renal routes. 

Colchicine is an alkaloid of Colchicum autumnale. Colchicine can produce dramatic relief from acute gout. Its mechanism of action is based on disappearance of microtubules in granulocytes, thereby inhibiting their migratory capacity, which is brought forward by the ability of colchicine to bind to tubulin. Colchicine is rapidly absorbed after oral administration and then metabolized to several metabolites which are excreted in the bile. Elimination from the body is slow. 

Colchicine is rapidly absorbed after oral administration and tends to concentrate in the spleen, kidney, liver, and gastrointestinal tract. Leukocytes also avidly accumulate and store colchicine even after a single intravenous injection. Since colchicine can accumulate in cells against a concentration gradient, it is postulated that an active transport process may be involved in its cellular uptake. The drug is metabolized, primarily in the liver, by deacetylation. Fecal excretion plays a major role in colchicine elimination, since it and its metabolites are readily secreted into the bile. Only about 15 to 30% of the drug is eliminated in the urine except in patients with liver disease urinary excretion is more important in these individuals. 

Transient diabetes and hyperlipidemia have been reported. Metabolic acidosis is probably a consequence of heavy, cholera-like diarrhea. Progressive reduction of libido was attributed to colchicine in patients with familial Mediterranean fever (312). 

Colchicine does not influence the renal excretion of uric acid or its concentration in blood. By virtue of its ability to bind to tubulin, colchicine interferes with the function of the mitotic spindles and causes depolymerization and disappearance of the fibrillar microtubules in granulocytes and other motile cells. This action is apparently the basis for the beneficial effect of colchicine, namely, the inhibition of the migration of granulocytes into the inflamed area and a decreased metabolic and phagocytic activity of granulocytes. This reduces the release of lactic acid and proinflammatory enzymes that occurs during phagocytosis and breaks the cycle that leads to the inflammatory response. 

Colchicine is metabolized to a mixture of compounds in vitro. Most of the drug is excreted in the feces however, in normal individuals, 10 to 20% of the drug is excreted in the urine. In patients with liver disease, hepatic uptake and elimination are reduced and a greater fraction of the drug is excreted in the urine. 

Substances that can be metabolized to y-diketones, such as -hexane, which is metabolized to 2,5-hexanedione, cause the same disorders. Examples of the many other substances known to cause axonopathies are colchicine, disulhram, hydralazine, misonidazole, and insecticidal pyrethroids. Peripheral neuropathy is the most common kind of axonopathic disorder. However, other symptoms may be observed. Numerous cases of manic psychoses were produced in workers exposed to carbon disulfide, CS2, in the viscose rayon and vulcan rubber industries. 

Gout is a metabolic disease in which there is a overproduction of purines. It is characterized by intermittent attacks of acute arthritis produced by the deposition of sodium urate crystals in the synovial tissue of joints. Drugs used for treating gout are allopurinol, probenecid, colchicine, and NSAIDs. 

A third focus has been directed toward incorporation of conventional PET radionuclides nC or 18F into existing substrates or inhibitors known to interact with Pgp [113-115]. This strategy has been employed to produce various PET agents, including 1 -colchicine, 11C-verapamil, nC-daunomycin, and uC/18F-paclitaxel[115-123]. While promising data have been generated, some of these PET agents suffer from modest radiochemical yields and others from complex pharmacokinetics in vivo mediated, at least in part, by rapid metabolism of the radiolabeled compounds. 

Henderson, A.J., Peaker, M. 1980. The effects of colchicine on milk secretion, mammary metabolism and blood flow in the goat. Quart. J. Exp. Physiol. 65, 367-378. 

COLCHICINE MACROLIDES Case reports of colchicine toxicity when macrolides were added Uncertain macrolides possibly inhibit hepatic metabolism of colchicine. Clarithromycin and erythromycin both inhibit intestinal P-gp, which may t bioavailability of colchicine Monitor FBC and renal function closely... 

The Sertoli cell plays a key metabolic role in the processes of germ cell development. Compounds that disrupt Sertoli cell metabolism would be expected to cause testicular toxicity. For example, 1,3-dinitro-benzene and other nitroaromatic compounds cause testicular toxicity apparently by disruption of Sertoli cell function. These compounds can undergo reductive metabolism to toxic nitroso intermediates, which may be ultimately responsible for the Sertoli cell toxicity. As indicated above, microtubules play an important role in support and transport processes. Hexanedione has been studied extensively as an agent capable of altering testicular microtubules. Other compounds that disrupt microtubule assembly and Sertoli cell function include the fungicide ben-omyl and the antiinflammatory agent colchicine, both of which prevent the assembly of testicular tubulin into microtubules. 

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