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外観
白色～灰色～褐色粉末～結晶
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効能
喘息治療薬, ロイコトリエン受容体拮抗薬
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説明
Accolate was launched in Ireland, Finland and the US for treatment of
asthma. Prepared via an eight step synthesis from methyl 3-methoxy-4-
methylbenzoate, zafirlukast acts as a LTD4 antagonist and is the first compound of a
new class of drugs. LTC4, LTD4 and LTE4 were determined to be the constituents of
the slow-reacting substance of anaphylaxis (SRS-A) which was found to induce
asthma effects (bronchoconstriction, increased vascular permeability resulting in
edema, cellular infiltration of airway tissues and decreased mucociliary transport).
Thus an inhibitor of their synthesis would at least attenuate these symptoms.
Zafirlukast binds to the CysLT receptor LT-1 and blocks the effect of LTC4, LTD4 and
LTE4. The drug is an oral twice daily formulation that reversed an LTD4 challenge,
attenuated the response of platelet-activating factor (PAF), an allergen and cold air
challenge and exercise-induced asthma.
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化学的特性
Off-white to pale pink crystalline solid
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使用
Zafirlukast has been used to stimulate pancreatic β cell line (MIN6) and pancreatic islets for insulin secretion assay. It may be used as an adenosine triphosphate-binding cassette transporter (ABCG2) inhibitor in MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxicity assay in human embryonic kidney cells (HEK293) and in Kirby-Bauer disc diffusion assays, bactericidal activity and minimal inhibitory concentration (mIC) assay against M. smegmatis
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獲得抵抗性
Zafirlukast inhibits CYP3A4 and
CYP2C9 in concentrations equivalent to clinical plasma levels and, therefore, should be used
with caution in patients taking drugs metabolized by these enzymes. Specifically,
coadministration with warfarin results in a significant increase in prothrombin time. Other drugs
metabolized by CYP2C9 are phenytoin and carbamazepine. In
addition, CYP3A4-metabolized drugs are cyclosporine, cisapride, and the dihydropyridine class of
calcium channel blockers. Of particular interest is the fact that aspirin increases the plasma
levels of zafirlukast, and theophylline decreases the plasma levels of zafirlukast. Care should be
taken when coadministering with erythromycin, because this decreases the bioavailability of
zafirlukast.
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臨床応用
Zafirlukast is an indole derivative with a sulfonamide group that fulfills the need for an ionizable
moiety on the pharmacophore. A large number of analogues have been prepared; however, they
all resulted in a decrease in antagonist activity. Zafirlukast, like montelukast, is a selective
antagonist for the cysLT1 receptor and antagonizes the bronchoconstrictive effects of all
leukotrienes (LTC4, LTD4, and LTE4).
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代謝
Zafirlukast is well absorbed orally; however, food will
decrease its absorption by as much as 40%. Zafirlukast is primarily metabolized in the liver by
CYP2C9 and CYP3A4 to hydroxylated metabolites. Zafirlukast also has been shown to
undergo carbamate hydrolysis, followed by N-acetylation. Additionally, zafirlukast in known to
produce an idiosyncratic hepatotoxicity in susceptible patients. This is appears to result from the
formation of an electrophilic α,β-unsaturated iminium intermediate evidenced by the formation of
a glutathione adduct on the methylene carbon bridging the indole ring to the methoxybenzene
moiety of the molecule. More than 90% if its metabolites are
excreted in the feces, with the remaining found in the urine.
