Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Colchicine is an alkaloid drug commonly used in familial Mediterranean fever (FMF), gout, Behcet's syndrome, psoriasis and Sweet's syndrome. The exact mechanism of its action in these diseases is not entirely known. However, it has been shown that colchicine may inhibit neutrophil chemotaxis, thereby decreasing the inflammatory process. Recently, it was shown that colchicine accumulates in neutrophils in higher concentrations than in lymphomonocytes. Studies dealing with the multiple drug resistance (MDR) issue disclosed that neutrophils lack the P-glycoprotein (P-gly) membranal pump (encoded by the MDR1 gene). We propose that the preferential accumulation of colchicine in neutrophils compared with lymphomonocytes is due to the absence of the P-gly efflux pump in the former. This may explain the effectiveness of colchicine in diseases where increased chemotaxis is evident. The hypothesis may also provide an explanation for FMF patients who do not respond to the drug.
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PMID:Does the lack of the P-glycoprotein efflux pump in neutrophils explain the efficacy of colchicine in familial Mediterranean fever and other inflammatory diseases? 984 64

Colchicine is used chiefly in the treatment of gout but is also valuable in other inflammatory diseases such as familial Mediterranean fever (FMF). Three proteins play pivotal roles in colchicine pharmacokinetics: the colchicine receptor, tubulin, which governs the plasma elimination half-life of the drug; intestinal and hepatic CYP3A4, which is key to the biotransformation of colchicine; and P-glycoprotein, a cell efflux pump that regulates the tissue distribution of colchicine, as well as its excretion via the biliary tract and kidneys. Pharmacokinetic studies have been performed using a radioimmunology assay to measure blood colchicine levels. Absorption after oral ingestion varies widely (from 24% to 88% of the dose), the volume of distribution is extremely large (7 l/kg), and binding to albumin is moderate. Colchicine is excreted chiefly through the liver and has an elimination half-life of 20-40 hours. With repeated doses of about 1mg/day, the steady-state is achieved within 8 days and concentrations range from 0.3 to 2.5 ng/ml. Studies of associations between pharmacokinetic parameters and pharmacodynamics show that effects are correlated, not to plasma levels, but to levels in leukocytes. Adverse events are not uncommon, most notably when colchicine is used in combination with drugs that interact with CYP3A4 and/or P-glycoprotein, thereby decreasing the renal and/or hepatic elimination of colchicine. Careful monitoring in this situation is effective in preventing the development of toxicity.
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PMID:Colchicine today. 1706 38

Introduction. Therapeutic doses of colchicine in patients with renal compromise and cyclosporine therapy may result in increased plasma concentrations of colchicine and colchicine toxicity. Case Report. A 60-year-old heart transplant patient with chronic renal failure and cyclosporine-induced immunosuppression was started on colchicine for suspected gout. Four days later, he developed multi-organ failure with rhabdomyolysis, liver damage, polyneuropathy, and cardiotoxicity. Colchicine intoxication was suspected and plasma levels were 7 ng/mL 36 hours after the sixth dose. Neutropenia with an absolute neutrophil count of 700 cells/mm3 was observed five days after colchicine discontinuation. Drug discontinuation, supportive care, antibiotic therapy for a concurrent infection, and G-CSF administration resulted in recovery and he was discharged from the hospital 3 weeks later. Discussion. Cyclosporine co-administration increases colchicine toxicity by a dual mechanism: cyclosporine inhibits P-glycoprotein resulting in increased intracellular colchicine concentrations and decreased hepatic and renal excretion of the drug and cyclosporine interacts with CYP3A4 to decreases the hepatic elimination of colchicine. On the other hand, colchicine may increase cyclosporine neurotoxicity by an addictive mechanism. Conclusions. Shortterm administration of therapeutic colchicine doses may cause life-threatening side effects in cyclosporine-treated patients with renal failure.
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PMID:Colchicine-induced toxicity in a heart transplant patient with chronic renal failure. 1860 82

New light has been shed on the mechanisms of action of colchicine in crystal-associated arthropathies. 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.
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PMID:Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. 1863 31

(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 diarrhoea, the earliest sign in patients with renal failure and in the elderly.
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PMID:Colchicine: serious interactions. 1949 85

Drug transporters significantly influence drug pharmacokinetics and pharmacodynamics. While P-glycoprotein, the product of the MDR1 (ABCB1) gene, is the most well-characterized ABC transporter, the pharmacological importance of a related transporter, ABCG2, is starting to be realized in veterinary medicine. Based primarily on human and rodent studies, a number of clinically relevant, structurally and functionally unrelated drugs are substrates for ABCG2. ABCG2 is expressed by a variety of normal tissues including the intestines, renal tubular cells, brain and retinal capillary endothelial cells, biliary canalicular cells, and others, where it functions to actively extrude substrate drugs. In this capacity, ABCG2 limits oral absorption of substrate drugs and restricts their distribution to privileged sites such as the brain and retina. ABCG2 is also expressed by tumor cells where it functions to limit the intracellular accumulation of cytotoxic agents, contributing to multidrug resistance. Several ABCG2 polymorphisms have been described in human patients, some of which result in altered drug disposition, increasing susceptibility to adverse drug reactions. Additionally, ABCG2 polymorphisms in humans have been associated with disease states such as gout. Feline ABCG2 has recently been demonstrated to have several amino acid differences at conserved sites compared with 10 other mammalian species. These amino acid differences adversely affect transport function of feline ABCG2 relative to that of human ABCG2. Furthermore, these differences appear to be responsible for fluoroquinolone-induced retinal toxicity in cats and may play a role in acetaminophen toxicity as well. Studies in rodents and sheep have determined that ABCG2 expressed in mammary tissue is responsible for the secretion of many compounds (both therapeutic and toxic) into milk. Finally, data in rodent models suggest that ABCG2 may play an important role in regulating a number of physiologic pathways involved in protecting erythrocytes from oxidative damage.
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PMID:ABCG2 transporter: therapeutic and physiologic implications in veterinary species. 2164 15

Using colchicine to treat an acute gout crisis in an organ transplant recipient (TR) on cyclosporine (CsA) may result in life-threatening intoxication. We report the case of a 59-year-old kidney transplant recipient on CsA who was treated with colchicine for acute gout crisis. Seven days later, he developed rhabdomyolysis with progressive quadriparesis, hematologic toxicity and acute renal failure. CsA inhibits P-glycoprotein resulting in decreased hepatic metabolism and renal excretion of colchicine. Colchicine and CsA withdrawal as well as appropriate supportive treatments were effective to manage all of these complications.
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PMID:Severe colchicine intoxication in a renal transplant recipient on cyclosporine. 2314 40