Identification and relative contributions of human cytochrome P450 isoforms involved in the metabolism of glibenclamide and lansoprazole:: evaluation of an approach based on the in vitro substrate disappearance rate

被引：47

作者：

Naritomi, Y ^{[1
]}

Terashita, S ^{[1
]}

Kagayama, A ^{[1
]}

机构：

[1] Fujisawa Pharmaceut Co Ltd, Biopharmaceut & Pharmacokinet Res Labs, Yodogawa Ku, Osaka 5328514, Japan

来源：

XENOBIOTICA | 2004年 / 34卷 / 05期

关键词：

D O I：

10.1080/00498250410001685728

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

1. The identification and relative contributions of human cytochrome P450 (CYP) enzymes involved in the metabolism of glibenclamide and lansoprazole in human liver microsomes were investigated using an approach based on the in vitro disappearance rate of unchanged drug. 2. Recombinant CYP2C19 and CYP3A4 catalysed a significant disappearance of both drugs. When the contribution of CYPs to the intrinsic clearance (CL int ) of drugs in pooled human microsomes was estimated by relative activity factors, contributions of CYP2C19 and CYP3A4 were determined to be 4.6 and 96.4% for glibenclamide, and 75.1 and 35.6% for lansoprazole, respectively. 3. CL int of glibenclamide correlated very well with CYP3A4 marker activity, whereas the CL int of lansoprazole significantly correlated with CYP2C19 and CYP3A4 marker activities in human liver microsomes from 12 separate individuals. Effects of CYP-specific inhibitors and anti-CYP3A serum on the CL int of drugs in pooled human liver microsomes reflected the relative contributions of CYP2C19 and CYP3A4. 4. The results suggest that glibenclamide is mainly metabolized by CYP3A4, whereas lansoprazole is metabolized by both CYP2C19 and CYP3A4 in human liver microsomes. This approach, based on the in vitro drug disappearance rate, is useful for estimating CYP identification and their contribution to drug discovery.

引用

页码：415 / 427

页数：13

共 29 条

[11]

Krausz KW, 2001, DRUG METAB DISPOS, V29, P1410

[12] 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

[13] Inhibition and induction of cytochrome P450 and the clinical implications [J].

Lin, JH ;

Lu, AYH .

CLINICAL PHARMACOKINETICS, 1998, 35 (05) :361-390

[14] Cytochrome P450 in vitro reaction phenotyping: A re-evaluation of approaches used for P450 isoform identification [J].

Lu, AYH ;

Wang, RW ;

Lin, JH .

DRUG METABOLISM AND DISPOSITION, 2003, 31 (04) :345-350

[15]

Nakajima M, 1999, DRUG METAB DISPOS, V27, P1381

[16]

Naritomi Y, 2001, DRUG METAB DISPOS, V29, P1316

[17] Utility of hepatocytes in predicting drug metabolism: Comparison of hepatic intrinsic clearance in rats and humans in vivo and in vitro [J].

Naritomi, Y ;

Terashita, S ;

Kagayama, A ;

Sugiyama, Y .

DRUG METABOLISM AND DISPOSITION, 2003, 31 (05) :580-588

[18] Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes [J].

Niemi, M ;

Cascorbi, I ;

Timm, R ;

Kroemer, HK ;

Neuvonen, PJ ;

Kivistö, KT .

CLINICAL PHARMACOLOGY & THERAPEUTICS, 2002, 72 (03) :326-332

[19]

Pearce RE, 1996, J PHARMACOL EXP THER, V277, P805

[20] HYDROXYLATION OF CHLORZOXAZONE AS A SPECIFIC PROBE FOR HUMAN LIVER CYTOCHROME-P-450IIE1 [J].

PETER, R ;

BOCKER, R ;

BEAUNE, PH ;

IWASAKI, M ;

GUENGERICH, FP ;

YANG, CS .

CHEMICAL RESEARCH IN TOXICOLOGY, 1990, 3 (06) :566-573

← 1 2 3 →