フェブキソスタット

外観

白色～ほとんど白色粉末～結晶

用途

フェブキソスタット（Febuxostat、開発コードTMX-67）は、非プリン型のキサンチンオキシダーゼ阻害薬である。痛風、高尿酸血症、またはがん化学療法に伴う高尿酸血症の治療薬として帝人ファーマが開発した。尿酸産生を抑制し、痛風発作を予防する。

効能

痛風治療薬, 尿酸生合成抑制薬, キサンチンオキシダーゼ阻害薬

商品名

フェブリク (帝人ファーマ)

説明

Febuxostat, a selective xanthine oxidase inhibitor, was launched for the chronic management of hyperuricemia in patients with gout. Hyperuricemia is defined as a serum uric acid concentration exceeding the limit of solubility. It predisposes affected persons to gout, a disease characterized by the formation of crystals of monosodium urate or uric acid from supersaturated fluids in joints and other tissues. Crystal deposition is asymptomatic, but it is revealed by bouts of joint inflammation. If left untreated, further crystals accumulate in joints and can form deposits known as tophi. A major aim in gout management is the long-term reduction of serum uric acid concentrations below saturation levels, as this results in crystal dissolution and eventual disappearance.
Febuxostat is a nonpurine derivative with higher potency and selectivity than allopurinol for inhibiting xanthine oxidase. It completely inhibits human xanthine oxidase activity in the lung cancer cell line A549, whereas the activities of other enzymes involved in purine or pyrimidine metabolism (e.g., purine nucleoside phosphorylase, adenosine deaminase, and pyrimidine nucleoside phosphorylase) are affected by<4%.

化学的特性

Crystalline Solid

物理的性質

Febuxostat has low solubility. It is almost insoluble in acidic conditions, slightly soluble in neutral conditions, and slightly more soluble in alkaline conditions. It is not suitable for making injections, but it can be taken orally because of its high oil-water partition coefficient and strong ability to cross cell membranes.

使用

Febuxostat is a new generation xanthine oxidase inhibitor developed by Tejin Co. (Japan,) used clinically for for long-term treatment of hyperuicemia (gout,) a new and highly effective non-purine selective inhibitor of xanthine oxidase. 40-120 mg/day febuxostat was proven effective in lowering serum urate levels when administered to manage hyperuricemia in patients with gout. It is not recommended for gout patients without hyperuricemia.

製造方法

Febuxostat can be synthesized in a multistep sequence from 2,4-dicyanophenol, starting with the alkylation of the phenolic hydroxyl group with isobutyl bromide and potassium carbonate, followed by treatment with thioacetamide in hot dimethyl formamide to yield 3-cyano-4-isobutoxythiobenzamide. Cyclization of the thioamide group with 2-chloroacetoacetic acid ethyl ester in refluxing ethanol affords 2-(3-cyano-4-isoutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, which is hydrolyzed with sodium hydroxide to produce febuxostat.

一般的な説明

Febuxostat is a potent, non-purine compound, which inhibits the expression of cytokines/chemokines. It has also been reported to inhibit LPS-induced TNF-α, VCAM-1, MMP9 and MCP-1 expression.

臨床応用

Fabuxostat was discovered by Teijin Pharmaceuticals and licensed to TAP Pharmaceuticals (which is currently part of Takeda Pharmaceuticals) and was approved in the U.S. for the treatment of hyperuricemia in patients with gout. It is a once-daily non-purine based agent with potent inhibitory activity against xanthine oxidase. The safety profile of the drug also does not require dose adjustment for patients with mild to moderate renal or hepatic impairment. Febuxostat is the first new agent cleared for this indication in 40 years.

副作用

The incidence of adverse events such as dizziness, diarrhea, headache, and nausea with febuxostat was similar to allopurinol. Febuxostat is contraindicated in patients being treated with the xanthine oxidase substrates such as azathioprine, mercaptopurine, and theophylline.

Mode of action

Xanthine oxidase is the main enzyme promoting uric acid production. It works by non-competitively blocking the molybdenum pterin center, which is the active site of xanthine oxidase. Through highly selective inhibition of oxidized and reduced xanthine oxidase, Febuxostat can reduce the synthesis of uric acid, decreasing its concentration and effectively treating gout. Through liver metabolism, Xanthine oxidase does not rely on renal excretion, so patients with moderate to severe liver and kidney dysfunction do not need to reduce dosages. Febuxostat is a non-purine XOR inhibitor, so it is very safe.