BIOACTIVATION OF DAPSONE TO A CYTOTOXIC METABOLITE - INVITRO USE OF A NOVEL 2 COMPARTMENT SYSTEM WHICH CONTAINS HUMAN TISSUES

被引：26

作者：

RILEY, RJ ^{[1
]}

ROBERTS, P ^{[1
]}

COLEMAN, MD ^{[1
]}

KITTERINGHAM, NR ^{[1
]}

PARK, BK ^{[1
]}

机构：

[1] UNIV LIVERPOOL,DEPT PHARMACOL & THERAPEUT,POB 147,LIVERPOOL L69 3BX,ENGLAND

来源：

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY | 1990年 / 30卷 / 03期

基金：

英国惠康基金;

关键词：

D O I：

10.1111/j.1365-2125.1990.tb03793.x

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

1. A two compartment system, comprising two adjacent teflon chambers separated by a semi‐permeable membrane, has been devised with which to investigate the generation of drug metabolites that are toxic to human cells in vitro. 2. Compartment A contained a drug‐metabolising system (human liver microsomes +/− NADPH) and compartment B contained target cells (human mononuclear leucocytes). The semi‐permeable membrane retained protein (m.w. greater than 10,000) but allowed equilibration (within 1 h) of drug and drug metabolites, during which time cells remained viable. 3. Incubation of dapsone (100 microM) with human microsomal protein (2 mg ml‐1) and NADPH (1 mM) in compartment A caused cell death (8.7 +/− 1.8%) in compartment B, which was reduced significantly (P less than 0.05) by the addition of glutathione (500 microM). Dapsone in the absence of NADPH was not cytotoxic. 4. Chemical analysis showed the presence of dapsone hydroxylamine as the only stable metabolite in both compartment A (5.2 +/− 0.4% incubated drug) and compartment B (3.5 +/− 0.5%). 5. Irreversible binding of dapsone to cells was significantly (P less than 0.05) reduced by omission of NADPH (85 +/− 13 pmol/10(6) cells) or addition of glutathione (103 +/− 9) compared with control values (153 +/− 51). 1990 The British Pharmacological Society

引用

页码：417 / 426

页数：10