THE ROLE OF LIPOPHILICITY IN THE INHIBITION OF POLYMORPHIC CYTOCHROME-P450IID6 OXIDATION BY BETA-BLOCKING-AGENTS INVITRO

被引：26

作者：

FERRARI, S ^{[1
]}

LEEMANN, T ^{[1
]}

DAYER, P ^{[1
]}

机构：

[1] UNIV GENEVA,HOP CANTONAL,DIV CLIN PHARMACOL,24 RUE MICHELI DU CREST,CH-1211 GENEVA 4,SWITZERLAND

来源：

LIFE SCIENCES | 1991年 / 48卷 / 23期

关键词：

INVIVO PHENOTYPED CARRIERS; ADRENOCEPTOR ANTAGONISTS; LIVER-MICROSOMES; BUFURALOL 1'-HYDROXYLATION; GENETIC-POLYMORPHISM; O-DEMETHYLATION; ENZYMATIC BASIS; DRUG OXIDATION; METABOLISM; PHARMACOKINETICS;

D O I：

10.1016/0024-3205(91)90341-8

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The importance of lipophilicity as a determinant of the affinity of beta-adrenoceptor blocking agents for a specific human hepatic monooxy-genase - cytochrome P450IID6 (responsible for the debrisoquine-type of oxidation polymorphism) - was investigated in vitro by estimating the inhibition constants of a series of compounds in a microsomal system with monitoring of the kinetics of dextromethorphan O-demethylation. Lipophilicity is a key predictor of the affinity of beta-blocking drugs for cytochrome P450IID6 and of their potential to cause specific competitive drug interactions, but more complex structural factors appear to be important as well. A high lipophilicity is also a necessary, but not a sufficient condition for these compounds to be metabolized by cytochrome P450IID6.

引用

页码：2259 / 2265

页数：7

共 36 条

[1] COMPARISON OF BETA-ADRENOCEPTOR ANTAGONISTS AS MODULATORS OF DRUG-METABOLISM - EFFECT OF LIPOPHILICITY ON MICROSOMAL PHASE-I AND PHASE-II REACTIONS [J].

AHOKAS, JT ;

DAVIES, C ;

RAVENSCROFT, PJ .

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1984, 17 :S103-S105

[2] INHIBITION OF LIGNOCAINE METABOLISM BY BETA-ADRENOCEPTOR ANTAGONISTS IN RAT AND HUMAN-LIVER MICROSOMES [J].

ALASADY, SAH ;

BLACK, GL ;

LENNARD, MS ;

TUCKER, GT ;

WOODS, HF .

XENOBIOTICA, 1989, 19 (09) :929-944

[3] INHIBITION OF TOLBUTAMIDE METABOLISM BY SUBSTITUTED IMIDAZOLE DRUGS INVIVO - EVIDENCE FOR A STRUCTURE-ACTIVITY RELATIONSHIP [J].

BACK, DJ ;

TJIA, JF .

BRITISH JOURNAL OF PHARMACOLOGY, 1985, 85 (01) :121-126

[4] DEPENDENCE OF HYDROGEN-PEROXIDE FORMATION IN RAT-LIVER MICROSOMES ON THE MOLECULAR-STRUCTURE OF CYTOCHROME-P-450 SUBSTRATES - A STUDY WITH BARBITURATES AND BETA-ADRENOCEPTOR ANTAGONISTS [J].

BAST, A ;

GOOSSENS, PAL ;

SAVENIJECHAPEL, EM .

EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1989, 14 (02) :93-100

[5] INHIBITION OF ANTIPYRINE METABOLISM BY BETA-ADRENOCEPTOR ANTAGONISTS [J].

BAX, NDS ;

LENNARD, MS ;

TUCKER, GT .

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1981, 12 (06) :779-784

[6] THE CLINICAL IMPORTANCE OF CARDIOSELECTIVITY AND LIPOPHILICITY IN BETA-BLOCKERS [J].

CRUICKSHANK, JM .

AMERICAN HEART JOURNAL, 1980, 100 (02) :160-178

[7] ENZYMATIC BASIS OF THE DEBRISOQUINE SPARTEINE-TYPE GENETIC-POLYMORPHISM OF DRUG OXIDATION - CHARACTERIZATION OF BUFURALOL 1'-HYDROXYLATION IN LIVER-MICROSOMES OF INVIVO PHENOTYPED CARRIERS OF THE GENETIC DEFICIENCY [J].

DAYER, P ;

KRONBACH, T ;

EICHELBAUM, M ;

MEYER, UA .

BIOCHEMICAL PHARMACOLOGY, 1987, 36 (23) :4145-4152

[8] DEXTROMETHORPHAN O-DEMETHYLATION IN LIVER-MICROSOMES AS A PROTOTYPE REACTION TO MONITOR CYTOCHROME-P-450 DB1 ACTIVITY [J].

DAYER, P ;

LEEMANN, T ;

STRIBERNI, R .

CLINICAL PHARMACOLOGY & THERAPEUTICS, 1989, 45 (01) :34-40

[9] INTERINDIVIDUAL VARIATION OF BETA-ADRENOCEPTOR BLOCKING-DRUGS, PLASMA-CONCENTRATION AND EFFECT - INFLUENCE OF GENETIC STATUS ON BEHAVIOR OF ATENOLOL, BOPINDOLOL AND METOPROLOL [J].

DAYER, P ;

LEEMANN, T ;

MARMY, A ;

ROSENTHALER, J .

EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1985, 28 (02) :149-153

[10] BIOACTIVATION OF THE NARCOTIC DRUG CODEINE IN HUMAN-LIVER IS MEDIATED BY THE POLYMORPHIC MONOOXYGENASE CATALYZING DEBRISOQUINE 4-HYDROXYLATION (CYTOCHROME-P-450 DBL/BUFI) [J].

DAYER, P ;

DESMEULES, J ;

LEEMANN, T ;

STRIBERNI, R .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1988, 152 (01) :411-416

← 1 2 3 4 →