Colchicine elimination

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. 

This high incidence of gastrointestinal side effects may be circumvented by administering colchicine intravenously. Except in patients with renal insufficiency, the initial intravenous dose of colchicine is 2 mg. If relief is not obtained, an additional 1-mg dose may be given at 6 and 12 hours to a total dose of 4 mg for a specific attack. The colchicine should be diluted with 20 ruL normal saline before administration to minimize sclerosis of the vein. The intravenous administration of colchicine eliminates most of the gas-... 

SeidelA. 1985. Colchicine reduces uptake of 239Pu and 241 Am by rat liver but not their elimination. IntJ Nucl Med Biol 12(4) 339-340. 

Seitz and colleagues108 made 10-ethylcolchicide (138), a colchicine derivative, react with several dienophiles. The reaction of 138 with dimethyl acetylenedicarboxylate (57) afforded a single Diels-Alder adduct (139) which underwent a consecutive [3 + 2] cycloaddition with another equivalent of dimethyl acetylenedicarboxylate to give 140. The formal elimination of C2H6 afforded 141, whereas fragmentation led to 142 (equation 41). 

The disappearance of tritiated vindesine from the blood of rats has been reported to be biphasic, with half-life estimates of 15 min (distribution) and 10 hr (elimination) (59) it is likely that the prolonged elimination phase represents a hybrid between the second elimination phase described above for vincristine and the prolonged third phase evident on inspection of log concentration-time plots for vincristine in the rat. Biliary excretion contributes heavily to the elimination of vindesine in the rat. The bioavailability of vindesine in the rat appears to be very poor. The distribution of vincristine to different tissues in the mouse has been correlated with the estimated concentration of tubulin in the tissues (40). Tubulin concentration was measured by the capacity of a tissue to bind colchicine (40) comparable relationships between tissue concentrations of vincristine and colchicine binding capacity were observed for the dog and the monkey, but it should be emphasized that the correlations were based on the assumption that tissue tubulin content is closely similar in the mouse, dog, and monkey. 

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 absorbed readily after oral administration, reaches peak plasma levels within 2 hours, and is eliminated with a serum half-life of 9 hours. Metabolites are excreted in the intestinal tract and urine. 

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. 

Allopurinoi, as well as its accumulating metabolite, oxypurinol ( alloxanthine ), inhibits xanthine oxidase, which catalyzes urate formation from hypoxanthine via xanthine. These precursors are readily eliminated via the urine. Allopurinoi is given orally (300-800 mg/day). Apart from infrequent allergic reactions, it is well tolerated and is the drug of choice for gout prophylaxis. Gout attacks may occur at the start of therapy but they can be prevented by concurrent administration of colchicine (0.5-1.5 mg/day). 

The above-mentioned measures do not combat the cause(s) or eliminate the primary pathogenetic reactions (with a few exceptions). The general aim is to prevent progression of the disease, ideally until the cirrhosis comes to a halt. When such medication is administered effectively, complicative developments can also be prevented. Pathogenetic primary reactions often initiate a cascade of secondary mechanisms, in particular of a biochemical nature. This is true, for example, of the inhibition of concomitant cholestasis during the course of cirrhosis by ursodeoxycholic acid (97), the reduction in lipid peroxidation by silymarin, the inhibition of fibrogenesis by colchicine (82) or silymarin (sometimes with improved quality of life), and the elimination of hyperammonaemia by ornithine aspartate. (145) (s. p. 279)... 

Historically, insight into the role of Sertoli cell microtubules in promoting spermatogenesis has been gleaned from analyzing the actions of known microtubule disrupters in the testis. Both colchicine and taxol lead to defects in spermiation and residual body elimination, activities attributed to Sertoli cells (105-107). Because microtubules are present in all cells, however, these studies cannot rule out potential actions on other cellular targets, particularly on the germ cells themselves. 

Although colchicine is metabolized, the major route of elimination of conjugated drug is renal. 

D. Enhanced elimination. Because colchicine is highly bound to tissues, with a large volume of distribution, hemodialysis and hemoperfusion are ineffective. Colchicine undergoes enterohepatic recirculation, so repeat-dose charcoal might be expected to accelerate elimination, although this has not been documented. 

Cha (1998) plan for colchicine tandem Diels-Alder—HCN elimination (step 11) Diels-Alder reaction (step 14). 

FIGURE 5.2. Elimination of the retarding influence of colchicine treatment By the simultaneous exogenous application of AA on various growth and yield characters of Brassica dhinensis L. 

If the NHj group is eliminated first, as in the fusion of colchicine with potassium hydroxide, and the product is oxidised with permanganate, terephthalic and trimellitic (benzene 1 2 4-tricarboxylic) acids are formed, which should come from a third benzene ring. 

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