Zafirlukast Metabolism by Cytochrome P450 3A4 Produces an Electrophilic ,
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- 作者：Kelem Kassahun ; Konstantine Skordos ; Ian McIntosh ; Donald Slaughter ; George A. Doss ; Thomas A. Baillie ; and Garold S. Yost
- 刊名：Chemical Research in Toxicology
- 出版年：2005
- 出版时间：September 2005
- 年：2005
- 卷：18
- 期：9
- 页码：1427 - 1437
- 全文大小：247K
- 年卷期：v.18,no.9(September 2005)
- ISSN：1520-5010
文摘
Zafirlukast is a leukotriene antagonist indicated for the treatment of mild to moderateasthma, but the drug has been associated with occasional idiosyncratic hepatotoxicity.Structurally, zafirlukast is similar to 3-methylindole because it contains an N-methylindolemoiety that has a 3-alkyl substituent on the indole ring. The results presented here describethe metabolic activation of zafirlukast via a similar mechanism to that described for3-methylindole. NADP(H)-dependent biotransformation of zafirlukast by hepatic microsomesfrom rats and humans afforded a reactive metabolite, which was detected as its GSH adduct.Mass spectrometry and NMR data indicated that the GSH adduct was formed by the additionof GSH to the methylene carbon between the indole- and methoxy-substituted phenyl rings ofzafirlukast. The formation of this reactive metabolite in human liver microsomes was shownto be exclusively catalyzed by CYP3A enzymes. Evidence for in vivo metabolic activation ofzafirlukast was obtained when the same GSH adduct was detected in bile of rats given an ivor oral dose of the drug. On the basis of results with model peroxidases and of the structuresof product alcohols from incubations containing H218O, it appeared that zafirlukast underwentdehydrogenation by two sequential one-electron oxidations. In addition, zafirlukast proved tobe a mechanism-based inhibitor of CYP3A4 activity in human liver microsomes and inmicrosomes containing cDNA-expressed CYP3A4. The enzyme inhibitory property of zafirlukastwas selective for this enzyme among all of the P450 enzymes that were tested in human livermicrosomes. The inactivation was characterized by a KI of 13.4 
M and kinact of 0.026 min-1.In summary, zafirlukast dehydrogenation to an electrophilic 
,
-unsaturated iminiumintermediate may be associated with idiosyncratic hepatotoxicity and/or cause drug-druginteractions through inactivation of CYP3A4.
M and kinact of 0.026 min-1.In summary, zafirlukast dehydrogenation to an electrophilic ,-unsaturated iminiumintermediate may be associated with idiosyncratic hepatotoxicity and/or cause drug-druginteractions through inactivation of CYP3A4.