LUMIRACOXIB

Absorption

Rapidly absorbed following oral administration, with an absolute oral bioavailablity of 74%.

Toxicity

Single oral doses in mice and rats resulted in mortality and/or moribundity at doses of 600 mg/kg and 500 mg/kg, respectively. Single intraperitoneal doses in mice and rats results in mortality/moribundity at 750 mg/kg and 1000 mg/kg, respectively. The maximum non-lethal single oral and intraperitoneal dose in mouse was 300 mg/kg and 250 mg/kg, respectively. In the rat it was 150 mg/kg and 250 mg/kg, respectively.

Description

As a second-generation, selective cyclooxygenase (COX-2) inhibitor, lumiracoxib is devoid of the gastrointestinal issues that plague other non-selective, nonsteroidal, anti-inflammatory drugs (NSAIDs) that crossover to COX-1. As an inhibitor of the inducible COX-2 that is up-regulated in pathological processes of pain and inflammation, lumiracoxib blocks the conversion of arachidonic acid to prostaglandins, the mediators of the pathological effects. It’s mode of binding to COX-2 has been found to differ from the other selective COX-2 inhibitors; the carboxylic acid forms hydrogen bonds with Tyr-385 and Ser-530 in the catalytic site rather than seeking interactions within the larger hydrophobic side pocket. Since lumiracoxib is mainly metabolized by CYP2C9, a study evaluating the co-administration of lumiracoxib with fluconazole, a potent inhibitor of CYP2C9, was conducted, and it concluded that there was no need for lumiracoxib dose adjustment, since changes in the systemic exposure were not significant. No serious adverse effects were reported, but in the small number of cases where treatment was discontinued, Gastro intestinal (GI) and musculoskeletal complaints were common.

Description

Lumiracoxib is a selective inhibitor of COX-2 with IC₅₀ values of 0.13 and 67 μM for COX-2 and COX-1, respectively, in isolated human whole blood. It reduces increases in the levels of prostaglandin E₂ (PGE₂; ) induced by IL-1β in human dermal fibroblasts (IC₅₀ = 0.14 μM), as well as in LPS-stimulated RAW 264.7 cells when used at concentrations ranging from 1 to 100 μM., Lumiracoxib (3 and 10 mg/kg) also decreases LPS-induced increases in the levels of PGE₂ in a rat model of air pouch inflammation. It reduces M. tuberculosis-induced increases in hind paw volume and the radiological and histopathological severity of arthritic lesions in a rat model of chronic arthritis when administered at a dose of 2 mg/kg.

Chemical properties

Pale Yellow Solid

Originator

Novartis AG (Switzerland)

The Uses of LUMIRACOXIB

Lumiracoxib is a selective cyclooxygenase-2-(COX-2) inhibitor and an anti-inflammatory agent (1,2,3,4).

The Uses of LUMIRACOXIB

Selective cyclooxygenase-2-(COX-2) inhibitor. Anti-inflammatory.

The Uses of LUMIRACOXIB

antiinflammatory, analgesic, antiarthritic

Background

Lumiracoxib is a COX-2 selective non-steroidal anti-inflammatory drug (NSAID). On August 11, 2007, Australia's Therapeutic Goods Administration (TGA, the Australian equivalent of the FDA) cancelled the registration of lumiracoxib in Australia due to concerns that it may cause liver failure. New Zealand and Canada have also followed suit in recalling the drug.

Indications

For the acute and chronic treatment of the signs and symptoms of osteoarthritis of the knee in adults.

What are the applications of Application

Lumaricoxib is a Cox-2 selective inhibitor and NSAID

Definition

ChEBI: An amino acid that is phenylacetic acid which is substituted at position 2 by the nitrogen of 2-chloro-6-fluoroaniline and at position 5 by a methyl group. A highly selective cyclooxygenase 2 inhibitor, it was briefly used for the treatment of osteoarthrit s, but was withdrawn due to concersns of hepatotoxicity.

brand name

Prexige

Biochem/physiol Actions

Lumiracoxib (COX189) is an orally active, potent and selective cyclooxygenase-2 inhibitor (Ki = 60 nM/COX-2 vs. 3.2 μM/COX-1) that inhibits COX-2-mediated PGE2 production in human whole blood (IC50 = 130 nM; stimulation = 50 μM A23187), but not COX-1-dependent TxB2 production (IC50 = 67 μM; stimulation = 10 μg/mL LPS). Lumiracoxib shows in vivo anti-inflammatory efficacy against carrageenan-induced paw oedema (ED30 = 0.35 mg/kg p.o.), CFA-induced hyperalgesia (ED30 = 5.1 mg/kg p.o.), as well as adjuvant-induced arthritis (ED50 = 3 mg/kg/day p.o.) in rats in vivo.

Pharmacokinetics

Lumiracoxib has a different structure from the standard COX-2 inhibitors (e.g. celecoxib). It more closely resembles the structure of diclofenac (one chlorine substituted by fluorine, the phenylacetic acid has another methyl group in meta position), making it a member of the arylalkanoic acid family of NSAIDs. It binds to a different site on the COX-2 receptor than the standard COX-2 inhibitors. It displays extremely high COX-2 selectivity.

Metabolism

Hepatic oxidation and hydroxylation via CYP2C9. Three major metabolites have been identified in plasma: 4'-hydroxy-lumiracoxib, 5-carboxy-lumiracoxib, and 4'-hydroxy-5-carboxy-lumiracoxib.