POTENT INHIBITION OF YEAST-EXPRESSED CYP2D6 BY DIHYDROQUINIDINE, QUINIDINE, AND ITS METABOLITES

被引：41

作者：

CHING, MS ^{[1
]}

BLAKE, CL ^{[1
]}

GHABRIAL, H ^{[1
]}

ELLIS, SW ^{[1
]}

LENNARD, MS ^{[1
]}

TUCKER, GT ^{[1
]}

SMALLWOOD, RA ^{[1
]}

机构：

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

来源：

BIOCHEMICAL PHARMACOLOGY | 1995年 / 50卷 / 06期

基金：

英国医学研究理事会;

关键词：

CYTOCHROME P450 2D6; METABOLIC INHIBITION; QUINIDINE; DIHYDROQUINIDINE; QUINIDINE METABOLITES;

D O I：

10.1016/0006-2952(95)00207-G

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The inhibitory effects of dihydroquinidine, quinidine and several quinidine metabolites on cytochrome P450 2D6 (CYP2D6) activity were examined. CYP2D6 heterologously expressed in yeast cells O-demethylated dextromethorphan with a mean K-m of 5.4 mu M and a V-max of 0.47 nmol/min/nmol. Quinidine and dihydroquinidine both potently inhibited CYP2D6 metabolic activity (mean K-i = 0.027 and 0.013 mu M, respec tively) in yeast microsomes and in human liver microsomes. The metabolites, 3-hydroxyquinidine, O-desmethylquinidine and quinidine N-oxide also inhibited CYP2D6, but their K-i values (0.43 to 2.3 mu M) were one to two orders of magnitude weaker than the values for quinidine and dihydroquinidine. There was a trend towards an inverse relationship between K-i and lipophilicity (r = -0.90, N = 5, P = 0.07), as determined by the retention-time parameter k' using reverse-phase HPLC. Thus, although the metabolites of quinidine have the capacity to inhibit CYP2D6 activity, quinidine and the impurity dihydroquinidine are the important inhibitors of CYP2D6.

引用

页码：833 / 837

页数：5

共 25 条

[1] COMPARATIVE EFFECTS OF THE DIASTEREOISOMERS, QUININE AND QUINIDINE IN PRODUCING PHENOCOPY DEBRISOQUINE POOR METABOLIZERS (PMS) IN HEALTHY-VOLUNTEERS [J].