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

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

There are many potential drug interactions that involve the complex cytochromes P450 (CYP) enzyme system when treatments for chronic inflammatory rheumatic diseases are used. This iatrogenic risk is increased in patients taking multiple drugs such as those with rheumatoid arthritis or gout, whatever the type of CYP interaction (substrate, inducer, or inhibitor of one of the CYP isoenzymes). Some of these CYP interactions may have clinical consequences, sometimes serious (overdose or therapeutic failure) and are often unrecognized by clinicians. The aim of this article is first of all to act as a reminder of the metabolic role of membrane-bound CYP enzymes in the liver in the oxidation of drugs and the potential types of interaction (drug substrate, inducer, or inhibitor or indirectly by the modulation of CYP activity through its powerful antiinflammatory activity). Secondly, the different factors that modulate the enzymatic activity of CYP will be described that may contribute to variations in drug metabolism and therefore modify the benefit-risk ratio of the drug. Thirdly, an analysis based on a review of the literature will present the different known interactions via CYP for drugs used in clinical practice in rheumatic diseases: analgesics, antiinflammatory drugs, conventional disease-modifying antirheumatic drugs and biologic agents. To limit the clinical consequences of these CYP interactions, it is recommended to focus on drugs that are really essential, to systematically identify the rheumatic patients most at risk before prescribing, and thus to adopt therapeutic strategies that reduce iatrogenic risk.
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PMID:Cytochrome P450 interactions and clinical implication in rheumatology. 2492 6