Showing papers by "B.K. Park published in 1989"
TL;DR: Measurement of urinary 6β-hydroxycortisol provides a simple non-invasive method with which to monitor the time-course of enzyme induction by drugs in man, but the method cannot be used to predict clinically important drug interactions until the cytochrome P-450 enzyme responsible for cortisol 6 β-hydroxylation has been fully characterized.
Abstract: The effect of enzyme induction by antipyrine, phenobarbitone and rifampicin on the time-course of urinary 6β-hydroxycortisol (6β-OHC) excretion was investigated in healthy volunteers. The drugs were given chronically for either seven or 14 days.
109 citations
TL;DR: Using human mononuclear leucocytes as target cells, the bioactivation of dapsone to a cytotoxic metabolite in the presence of microsomes from nine human livers was investigated and Cytotoxicity was abolished not only by ascorbic acid, but also by sub-physiological concentrations of N-acetylcysteine and glutathione.
Abstract: 1. Using human mononuclear leucocytes as target cells, we have investigated the bioactivation of dapsone (DDS) to a cytotoxic metabolite in the presence of microsomes from nine human livers. Values for NADPH dependent toxicity ranged from 8.8-27% (15.8 +/- 5.9%) and were similar to those for microsomes from control mice, 16-24% (19.0 +/- 4.8%). 2. Microsomes prepared from mice induced with either phenobarbitone or beta-naphthoflavone did not produce significantly more NADPH dependent toxicity than microsomes prepared from control mice. 3. Cytotoxicity was abolished not only by ascorbic acid, but also by sub-physiological concentrations of N-acetylcysteine and glutathione. 4. DDS was metabolised in vitro to a hydroxylamine (metabolic conversion 3.1 +/- 1.5%), which was oxidised further to a cytotoxic metabolite which also became irreversibly bound to protein.
70 citations
TL;DR: It is shown that AQ is immunogenic in the rat and that the formation of a chemically reactive metabolite (AQQI) is involved in the generation of the antibody response.
54 citations
TL;DR: Investigation of cytotoxic metabolites from the anticonvulsants phenytoin and carbamazepine found that molecules which contain either an amide function or an aryl ring may undergo activation in vitro, but only the metabolism-dependent toxicity of the latter is potentiated by pre-treatment of the target cells with an epoxide hydrolase inhibitor.
Abstract: The formation of cytotoxic metabolites from the anticonvulsants phenytoin and carbamazepine was investigated in vitro using a hepatic microsomal enzyme system and human mononuclear leucocytes as target cells Both drugs were metabolised to cytotoxic products In order to assess the structural requirements for this bioactivation, a series of structurally related compounds was investigated It was found that molecules which contain either an amide function or an aryl ring may undergo activation in vitro, but only the metabolism-dependent toxicity of the latter is potentiated by pre-treatment of the target cells with an epoxide hydrolase inhibitor Taken collectively, these data are consistent with the concept that reactive epoxide metabolites of both phenytoin and carbamazepine may produce toxicity in individuals with an inherited deficiency in epoxide hydrolase
38 citations
TL;DR: Inhibition of irreversible binding was demonstrated with sodium cyanide at concentrations which did not inhibit total metabolism, which suggest that metabolic activation by the cytochrome P-450 enzyme system may lead to the formation of a reactive iminium intermediate that can bind to nucleophilic groups on proteins.
21 citations
TL;DR: The metabolism of the enantiomers of mianserin to stable, chemically reactive and cytotoxic metabolites by human liver microsomes has been investigated in vitro and showed a significant correlation with N-demethylation.
Abstract: 1. The metabolism of the enantiomers of mianserin to stable, chemically reactive and cytotoxic metabolites by human liver microsomes has been investigated in vitro. 2. Both enantiomers were metabolised to three major oxidation products: 8-hydroxymianserin, desmethylmianserin and mianserin 2-oxide. Hydroxylation occurred more readily with the S-enantiomer, whereas desmethylmianserin was always the major metabolite of the R-enantiomer. 3. The generation of chemically reactive metabolites exhibited a marginal degree of stereoselectivity, as assessed by irreversible binding of drug to microsomal protein (S greater than or equal to R; P less than or equal to 0.05). 4. The formation of metabolites which were cytotoxic towards human mononuclear leucocytes was greater (P less than or equal to 0.001] for R(-)-mianserin than for S(+)-mianserin and showed a significant correlation with N-demethylation (r = 0.84, P less than or equal to 0.01).
14 citations