Karty Mechanism of Action

Pharmacology: Pharmacodynamics: The mechanism of action differs from the nonsteroidal anti inflammatory drugs since it is not related to the inhibition of the synthesis of the prostaglandins. Antiosteoarthritic and cartilage-stimulating properties have been demonstrated in vitro and in animal models. Diacerein and its active metabolite have been shown to inhibit the production of interleukin-1 beta by human monocytes and the effects of the cytokine on chondrocytes in vivo. They exert chondro protective effects in cultured articular cartilage and reduce severity of cartilage, bone, and synovial membrane damage in osteoarthritis. There appear to be some inhibitory effects on leucocyte migration and activation, contributing to the weak anti-inflammatory activity of the drug. Studies indicate that Diacerein does not block the synthesis of prostaglandins, thromboxanes, or leukotrienes but may actually stimulate prostaglandin synthesis, especially PGF-2 alpha, a prostaglandin with cytoprotective effect on the gastric mucosa.
Diacerein in therapeutic doses inhibits the stimulation of interleukin-1 beta production and production of nitrous oxide. It also significantly reduces severity of pathological changes of osteoarthritis compared to placebo and increases the expression of transforming growth factor (TGF)-beta1 and TGF-beta 2, with potential cartilage repairing properties. Diacerein does not alter renal or platelet cyclo-oxygenase activity and may therefore be tolerated by patients with prostaglandin-dependent renal function.
Pharmacokinetics: Absorption: Oral bioavailability of Diacerein is 35% to 56%. Concurrent intake of food delays the time to peak concentration from 2.4 hours to 5.2 hours (p less than 0.05), but is associated with a 25% increase in absorption. Therefore, Diacerein is best given with food.
Distribution: Total protein binding of the active metabolite is about 99% to plasma albumin and in a lesser percentage to lipoproteins and gamma-immunoglobulins. It achieves synovial fluid concentration of 0.3 to 3.0 milligrams/liter.
Metabolism: Diacerein is metabolized extensively (100%) in liver following oral dosing, to the deacetylated active metabolite rhein, prior to entering systemic circulation. Major active metabolites include rhein glucuronide and rhein sulfate with half-life being 7 to 8 hours.
Excretion: Urinary excretion of Diacerein in the form of its metabolites has ranged between 35% and 60%, with approximately 20% as free rhein and 80% as conjugates of rhein.