Arzneimittelforschung. 2002;52(9):684-8.
Improvement of the bioavailability of colchicine in rats by co-administration of D-alpha-tocopherol polyethylene glycol 1000 succinate and a polyethoxylated derivative of 12-hydroxy-stearic acid.

Bittner B, Guenzi A, Fullhardt P, Zuercher G, Gonzalez RC, Mountfield RJ.

Pharma Division, DMPK Discovery Support, F. Hoffmann-La Roche Ltd., Basel, Switzerland. beate.bittneoche.com

Two surface-active formulation ingredients, a water-soluble derivative of vitamin E (D-alpha-tocopherol polyethylene glycol 1000 succinate, vitamin E-TPGS) as well as a polyethoxylated derivative of 12-hydroxy-stearic acid (Solutol HS 15) were investigated in rats for their potential to increase the oral bioavailability of the p-glycoprotein (p-gp) and cytochrome P450 substrate colchicine. D-alpha-Tocopherol polyethylene glycol 1000 succinate and the polyethoxylated derivative of 12-hydroxy-stearic acid will be referred to as "surfactant 1" and "surfactant 2" in the following. Colchicine was administered to the animals at a dose level of 5 mg/kg in each 10% surfactant containing formulation. A solution of colchicine in isotonic saline was selected as a reference formulation. It was found that the administration of colchicine in the surfactant containing formulations resulted in significantly higher systemic exposures as compared to the aqueous reference vehicle (2-fold increase in AUC in the presence of surfactant 1 and 4-fold increase in AUC in the presence of surfactant 2). The aqueous solubility of colchicine was about 16.7 mg/ml, and the increase in solubility in the presence of 1% surfactant 1 or surfactant 2 to about 20.5 and 18.5 mg/ml was not considered to significantly affect the oral bioavailability. In summary, it was demonstrated that both surfactants are suitable formulation ingredients to improve the systemic exposure of colchicine in the rat. Due to the high aqueous solubility of colchicine the most likely reasons for these findings are inhibition of p-gp and/or metabolism as well as permeability enhancement by interactions of the surfactants with the intestinal membrane.


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ms.skh.org.tw

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.


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Clin Exp Immunol. 1989 Nov;78(2):230-2.
Inhibition of delayed hypersensitivity reactions by colchicine. II. Colchicine inhibits interferon-gamma induced expression of HLA-DR on gut epithelial cell line.

Mekori YA, Chowers Y, Ducker I, Klajman A.

Allergy-Immunology Unit, Meir Hospital, Kfar Saba, Israel.

The effects of colchicine and vinblastine on interferon-gamma (IFN-gamma) induced expression of HLA-DR antigens on the HT-29 colonic carcinoma cell line was investigated in vitro. Both drugs prevented the expression of HLA-DR only if applied before or together with IFN-gamma. Methotrexate, an antimitotic drug, failed to inhibit DR expression by these cells. Colchicine and vinblastine, but not methotrexate, act on the cellular microtubules, interfering with the transport of proteins from the protoplasm to the cell surface and thus preventing the appearance of HLA-DR antigens. The reported findings may explain the role of colchicine in preventing delayed hypersensitivity reactions.


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Brain Res. 2003 May 16;972(1-2):222-8.
Inter- and intra-nuclear differences in galanin expression between the hypothalamic paraventricular and supraoptic nuclei in colchicine-untreated rats.

Okere CO, Waterhouse BD.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA. chuma.okerrexel.edu

Not much is known of the topography of galanin expression in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei neurons in colchicine (an axoplasmic inhibitor)-untreated animals. Insight into the biological implication(s) of galanin expression in the PVN and SON will depend, at least in part, on the nature of its distribution in colchicine-untreated animals. In this study therefore, the topographical distribution of galaninergic profiles was examined in the PVN and SON of colchicine-untreated rats. Staining in the parvocellular PVN (PVN(p)) was predominantly as varicose thin galanin fiber processes while the magnocellular PVN (PVN(m)) contained large cell soma and fiber processes. The relative fiber density was higher in the anterior, periventricular and medial PVN(p) than in the dorsal, lateral and posterior subdivisions. Large-sized cells and thick fibers were limited to the posterior PVN(m) while the anterior and medial PVN(m) contained varicose profiles. Light- and intensely-stained galanin-positive cells as well as large- and small-diameter (varicose or non-varicose) fibers were observed in the SON. The large and thin fibers exhibit preferential ventral and dorsal distribution, respectively. Together with the complexity of specific afferent and efferent connections within the PVN and SON, these observations underscore heterogeneous galanin expression and raise potential implications for understanding the biological role of galanin by physiologically challenging stimuli.


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