スリンダク 化学特性,用途語,生産方法
外観
黄色〜黄褐色, 結晶〜粉末
溶解性
エタノール及びアセトンにやや溶けにくく、水にほとんど溶けない。
用途
インドール酢酸系化合物です。
スリンダクはプロドラックであり、活性代謝
物であるスルフィド体がCOX 阻害作用を示
します。
効能
鎮痛薬, 抗炎症薬, シクロオキシゲナーゼ阻害薬
商品名
クリノリル (日医工); クリノリル (日医工)
説明
Many non-
steroidal anti-
inflammatory drugs (NSAIDs) are potent but non-
selective inhibitors of both COX-
1 and COX-
2 in humans. Sulindac is one of the older NSAIDs, an isostere of indomethacin developed before the inducible form of COX-
2 was discovered. Although a number of NSAIDs have been found to protect against digestive tract cancers, sulindac has an extensive epidemiology documenting reduced human colorectal cancer. In murine models, sulindac was found not only to inhibit the enzymatic activity of polyp-
associated COX-
2, but also to downregulate the expression of colonic COX-
2 protein to control levels.
化学的特性
Yellow Crystalline Solid
使用
Sulindac is a non-steroidal anti-inflammatory drug.
定義
ChEBI: A monocarboxylic acid that is 1-benzylidene-1H-indene which is substituted at positions 2, 3, and 5 by methyl, carboxymethyl, and fluorine respectively, and in which the phenyl group of the benzylidene moiety is substituted at the
ara position by a methylsulfinyl group. It is a prodrug for the corresponding sulfide, a non-steroidal anti-inflammatory drug, used particularly in the treatment of acute and chronic inflammatory conditions.
適応症
Sulindac (Clinoril) is chemically related to indomethacin
and is generally used for the same indications.
It is a prodrug that is metabolized to an active sulfide
metabolite and an inactive metabolite. The most
frequently reported side effects are GI pain, nausea, diarrhea,
and constipation. The incidence of these effects
is lower than for indomethacin, presumably because
sulindac is a prodrug and thus the active metabolite is
not highly concentrated at the gastric mucosa. As with
indomethacin, a rather high incidence of CNS side effects
(dizziness, headache) also occurs.
一般的な説明
Sulindac, (Z)-5-fluoro-2-methyl-1-([p-(methylsulfinyl)phenyl]methylene)-1H-indene-3-acetic acid (Clinoril), isan NSAID prodrug that contains a chiral sulfoxide moietybut is marketed as the racemate because it undergoes invivo reduction by the hepatic enzymes into its achiral, activemetabolite, methyl sulfide that exhibits potent andnonselective COX inhibition similar to indomethacin.
The parent sulfoxide has a plasma half-life of 8 hours, andthe active methyl sulfide metabolite is 16.4 hours. The morepolar and inactive sulfoxide is virtually the only form excretedinto the renal tubules, thus sulindac is believed to haveminimal nephrotoxicity associated with indomethacin. Thelong half-life of sulindac is caused by the extensive enterohepaticcirculation and reactivation of the inactive sulfoxideexcreted. Coadministration of aspirin is contraindicated becauseit considerably reduces the sulfide blood levels. Carefulmonitoring of patients with a history of ulcers is recommended.Gastric bleeding, nausea, diarrhea, dizziness, andother adverse effects have been noted with sulindac, but witha lower frequency than with aspirin. Sulindac is recommendedfor RA, OA, and ankylosing spondylitis.
生物活性
Prodrug. Metabolizes to sulindac sulfide, a cyclooxgenase inhibitor that represses ras signaling, and sulindac sulfone, an antitumor agent, following oral administration in vivo . Widely used anti-inflammatory agent.
薬物動態学
Sulindac is well absorbed on oral administration (90%), reaches peak plasma levels within 2 to 4 hours, and being
acidic (pKa = 4.5), is highly bound to serum proteins (93%). The metabolism of sulindac plays a major role in its
actions, because all of the pharmacological activity is associated with its major metabolite. Sulindac is, in fact, a
pro-drug, the sulfoxide function being reduced to the active sulfide metabolite. Sulindac is absorbed as the sulfoxide,
which is not an inhibitor of prostaglandin biosynthesis in the GI tract. Prostaglandins exert a
protective effect in the GI tract, and inhibition of their synthesis here leads to many of the GI side effects noted for
most NSAIDs. Once sulindac enters the circulatory system, it is reduced to the sulfide, which is an inhibitor of
prostaglandin biosynthesis in the joints. Thus, sulindac produces less GI side effects, such as bleeding, ulcerations,
and so on, than indomethacin and many other NSAIDs. In addition, the active metabolite has a plasma half-life
approximately twice that of the parent compound (～16 hours versus 8 hours), which favorably affects the dosing
schedule. In addition to the sulfide metabolite, sulindac is oxidized to the corresponding sulfone, which is inactive. A
minor product results from hydroxylation of the benzylidene function and the methyl group at the 2-position.
Glucuronides of several metabolites also are found. Sulindac as well as the sulfide and the sulfone metabolites are
all highly protein-bound. Despite the fact that the sulfide metabolite is a major activation product and is found in high
concentration in human plasma, it is not found in human urine, perhaps because of its high degree of protein binding.
臨床応用
Sulindac is indicated for long-term use in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis,
and acute gouty arthritis. The usual maximum dosage is 400 mg/day, with starting doses recommended at 150 mg
twice a day. It is recommended that sulindac be administered with food.
副作用
Whereas the toxicity of sulindac is lower than that observed for indomethacin and other NSAIDs, the spectrum of
adverse reactions is very similar. The most frequent side effects reported are associated with irritation of the GI tract
(e.g., nausea, dyspepsia, and diarrhea), although these effects generally are mild. Effects on the CNS (e.g.,
dizziness and headache) are less common. Dermatological effects are less frequently encountered.
スリンダク 上流と下流の製品情報
原材料
準備製品