CHARACTERIZATION OF METRONIDAZOLE METABOLISM BY HUMAN LIVER-MICROSOMES

被引：33

作者：

LOFT, S ^{[1
]}

OTTON, SV ^{[1
]}

LENNARD, MS ^{[1
]}

TUCKER, GT ^{[1
]}

POULSEN, HE ^{[1
]}

机构：

[1] UNIV SHEFFIELD, ROYAL HALLAMSHIRE HOSP, DEPT MED & PHARMACOL, SHEFFIELD S10 2JF, S YORKSHIRE, ENGLAND

来源：

BIOCHEMICAL PHARMACOLOGY | 1991年 / 41卷 / 08期

关键词：

D O I：

10.1016/0006-2952(91)90650-T

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The metabolism of metronidazole was studied in microsomes isolated from livers of human kidney donors. The formation of the major in vivo metabolite, hydroxymetronidazole, proceeded according to biphasic kinetics, suggesting the involvement of at least two enzymatic sites. The affinity constant (K(m)) of the high affinity site ranged from 140 to 320-mu-M and metabolism at this site contributed more than 75% of the intrinsic clearance. Thus, at therapeutic doses of metronidazole most of the hydroxylation in vivo should be associated with this site. Antipyrine, cimetidine, alpha-naphthoflavone, caffeine, theophylline, mephenytoin, tolbutamide, quinidine, acetone and nifedipine were poor inhibitors of the formation of hydroxymetronidazole by human liver microsomes. Propranolol (500-mu-M) inhibited the hydroxylation rate by 70%. Phenacetin inhibited metronidazole hydroxylation with a competitive inhibition constant (K(i)) of 4-5-mu-M. However, metronidazole did not inhibit the Odeethylation of phenacetin. It is concluded that cytochromes P450 IA2, IIC9, IIC10, IID6, IIE1 and IIIA3 do not contribute significantly to the high affinity hydroxylation of metronidazole in man.

引用

页码：1127 / 1134

页数：8

共 36 条

[1] LACK OF INHIBITORY EFFECT OF METRONIDAZOLE ON THEOPHYLLINE DISPOSITION IN HEALTHY-SUBJECTS [J].