Effect of Ethanol on S-Warfarin and Diclofenac Metabolism by Recombinant Human CYP2C9.1

被引：12

作者：

Tatsumi, Akitoshi ^{[1
,3
]}

Ikegami, Yuki ^{[2
]}

Morii, Ryoko ^{[2
]}

Sugiyama, Masatoshi ^{[1
]}

Kadobayashi, Muneo ^{[3
]}

Iwakawa, Seigo ^{[2
]}

机构：

[1] Kobe Pharmaceut Univ, Educ Ctr Clin Pharm, Higashinada Ku, Kobe, Hyogo 6588558, Japan

[2] Kobe Pharmaceut Univ, Dept Pharmaceut, Higashinada Ku, Kobe, Hyogo 6588558, Japan

[3] Hosp Hyogo Coll Med, Dept Pharm, Nishinomiya, Hyogo 6638501, Japan

来源：

BIOLOGICAL & PHARMACEUTICAL BULLETIN | 2009年 / 32卷 / 03期

关键词：

warfarin; ethanol; cytochrome P450 2C9.1 microsome; diclofenac; drug interaction; metabolism; HUMAN LIVER-MICROSOMES; DRUG-INTERACTIONS; ACETONITRILE; ALCOHOL; SERUM;

D O I：

10.1248/bpb.32.517

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The effect of ethanol on the metabolism of S-warfarin and diclofenac by recombinant cytochrome P450 2C9.1 microsomes (CYP2C9.1) was studied. The 7-hydroxylation metabolism of S-warfarin was inhibited by as low as 0.1 vol% (17 mm) ethanol. Ethanol decreased the V-max/K-m and V-max values of S-warfarin metabolism in a concentration-dependent manner, but the K-m value was unchanged by ethanol. The inhibitory effect of ethanol on the 4'-hydroxylation metabolism of diclofenac was not observed even at 1.0 vol% (170 mM) ethanol. Ethanol at a concentration of 3.0 vol% (510 mM) increased the K-m value of diclofenac metabolism without changes in the V-max, which indicates that diclofenac 4'-hydroxylation by CYP2C9.1 was competitively inhibited by ethanol. S-Warfarin metabolism by CYP2C9.1 was more sensitive to ethanol than diclofenac metabolism. These results suggest that ethanol inhibits the metabolism by CYP2C9.1 in a substrate-dependent manner.

引用

页码：517 / 519

页数：3

共 17 条

[1] Hepatic metabolism of diclofenac:: Role of human CYP in the minor oxidative pathways [J].

Bort, R ;

Macé, K ;

Boobis, A ;

Gómez-Lechón, MJ ;

Pfeifer, A ;

Castell, J .

BIOCHEMICAL PHARMACOLOGY, 1999, 58 (05) :787-796

[2]

Busby WF, 1999, DRUG METAB DISPOS, V27, P246

[3] Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: Role of CYP2C isoforms in human liver microsomes [J].

Hamitouche, S. ;

Poupon, J. ;

Dreano, Y. ;

Amet, Y. ;

Lucas, D. .

TOXICOLOGY LETTERS, 2006, 167 (03) :221-230

[4] Clinically important drug interactions with anticoagulants - An update [J].

Harder, S ;

Thurmann, P .

CLINICAL PHARMACOKINETICS, 1996, 30 (06) :416-444

[5] Enhanced antithrombotic effect of warfarin associated with low-dose alcohol consumption [J].

Havrda, DE ;

Mai, T ;

Chonlahan, J .

PHARMACOTHERAPY, 2005, 25 (02) :303-307

[6]

HERSKOVI.TT, 1970, J BIOL CHEM, V245, P2588

[7] Effect of glimepiride and glibenclamide on S-warfarin 7-hydroxylation by human liver microsomes, recombinant human CYP2C9.1 and CYP2C9.3 [J].

Iwakawa, Seigo ;

Miyashita, Kenji ;

Hashimoto, Yasuaki ;

Kuroda, Tsutomu .

BIOLOGICAL & PHARMACEUTICAL BULLETIN, 2006, 29 (09) :1983-1985

[8] Human P450 metabolism of warfarin [J].

Kaminsky, LS ;

Zhang, ZY .

PHARMACOLOGY & THERAPEUTICS, 1997, 73 (01) :67-74

[9] Efficient high performance liquid chromatograph/ultraviolet method for determination of diclofenac and 4′-hydroxydiclofenac in rat serum [J].

Kaphalia, L ;

Kaphalia, BS ;

Kumar, S ;

Kanz, MF ;

Treinen-Moslen, M .

JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, 2006, 830 (02) :231-237

[10] CYTOCHROME-P450TB (CYP2C) - A MAJOR MONOOXYGENASE CATALYZING DICLOFENAC 4'-HYDROXYLATION IN HUMAN LIVER [J].

LEEMANN, T ;

TRANSON, C ;

DAYER, P .

LIFE SCIENCES, 1993, 52 (01) :29-34

← 1 2 →