Showing papers by "B.K. Park published in 1994"
TL;DR: Using cytochrome P450 isoform specific inhibitors CYP1A2 was identified as the major enzyme involved in all routes of THA metabolism and may provide a useful tool for examining the relationship between the metabolism and toxicity of ThA in vivo.
Abstract: 1. Tacrine (1,2,3,4-tetrahydro-9-aminoacridine-hydrochloride: THA) underwent metabolism in vitro by a panel (n = 12) of human liver microsomes genotyped for CYP2D6, in the presence of NADPH, to both protein-reactive and stable metabolites. 2. There was considerable variation in the extent of THA metabolism amongst human livers. Protein-reactive metabolite formation showed a 10-fold variation (0.6 +/- 0.1%-5.2 +/- 0.8% of incubated radioactivity mg-1 protein) whilst stable metabolites showed a 3-fold variation (24.3 +/- 1.7%-78.6 +/- 2.6% of incubated radioactivity). 3. Using cytochrome P450 isoform specific inhibitors CYP1A2 was identified as the major enzyme involved in all routes of THA metabolism. 4. There was a high correlation between aromatic and alicyclic hydroxylation (r = 0.92, P < 0.0001) consistent with these biotransformations being catalysed by the same enzymes. 5. Enoxacin (ENOX), cimetidine (CIM) and chloroquine (CQ) inhibited THA metabolism by a preferential decrease in the bioactivation to protein-reactive, and hence potentially toxic, species. The inhibitory potency of ENOX and CIM was increased significantly upon pre-incubation with microsomes and NADPH. 6. Covalent binding correlated with 7-OH-THA formation before (r = 0.792, P < 0.0001) and after (r = 0.73, P < 0.0001) inhibition by CIM, consistent with a two-step mechanism in the formation of protein-reactive metabolite(s) via a 7-OH intermediate. 7. The use of enzyme inhibitors may provide a useful tool for examining the relationship between the metabolism and toxicity of THA in vivo.
85 citations
TL;DR: F fluorine substitution at the 2',6'-positions and replacement of the 4'-hydroxyl of amodiaquine with fluorine produces analogues that maintain antimalarial efficacy in vitro and are more resistant to oxidation and hence less likely to form toxic quinone imine metabolites in vivo.
Abstract: Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial which causes adverse side effects such as agranulocytosis and liver damage. The observed drug toxicity is believed to be related to the formation of an electrophilic metabolite, amodiaquine quinone imine (AQQI), which can bind to cellular macro-molecules and initiate hypersensitivity reactions. 5'-Fluoroamodiaquine (5'-FAQ, 3), 5',6'-difluoroamodiaquine (5',6'-DIFAQ,4), 2',6'-difluoroamodiaquine (2',6'-DIFAQ,5), 2',5',6'-trifluoroamodiaquine (2',5',6'-TRIFAQ, 6) and 4'-dehydroxy-4'-fluoroamodiaquine (4'-deOH-4'-FAQ,7) have been synthesized to assess the effect of fluorine substitution on the oxidation potential, metabolism, and in vitro antimalarial activity of amodiaquine. The oxidation potentials were measured by cyclic voltammetry, and it was observed that substitution at the 2',6'- and the 4'-positions (2',6'-DIFAQ and 4'-deOH-4'-FAQ) produced analogues with significantly higher oxidation potentials than the parent drug. Fluorine substitution at the 2',6'-positions and the 4'-position also produced analogues that were more resistant to bioactivation. Thus 2',6'-DIFAQ and 4'-deOH-4'-FAQ produced thioether conjugates corresponding to 2.17% (SD: +/- 0.27%) and 0% of the dose compared with 11.87% (SD: +/- 1.31%) of the dose for amodiaquine. In general the fluorinated analogues had similar in vitro antimalarial activity to amodiaquine against the chloroquine resistant K1 strain of Plasmodium falciparum and the chloroquine sensitive T9-96 strain of P. falciparum with the notable exception of 2',5',6'-TRIFAQ (6). The data presented indicate that fluorine substitution at the 2',6'-positions and replacement of the 4'-hydroxyl of amodiaquine with fluorine produces analogues (5 and 7) that maintain antimalarial efficacy in vitro and are more resistant to oxidation and hence less likely to form toxic quinone imine metabolites in vivo.
78 citations
TL;DR: Prevention of metabolite-mediated toxicity is possible once the mechanism of toxicity has been elucidated and an imbalance between bioactivation of a drug to a toxic metabolite and its detoxification is of prime importance in determining individual susceptibility.
Abstract: Adverse drug reactions can be caused by the parent drug or a metabolite of that drug. The metabolite may be stable or chemically reactive, the resultant toxicity being either a direct extension of the pharmacology of the drug, or unrelated to the known pharmacology of the drug and dependent on the chemical properties of the compound. Many different organ systems may be affected, and there are several mechanisms involved in determining organ-specific, and sometimes cell-selective, toxicity. An imbalance between bioactivation of a drug to a toxic metabolite and its detoxification is of prime importance in determining individual susceptibility. Such an imbalance may be genetically determined or acquired and, furthermore, may be systemic or tissue-specific. Prevention of metabolite-mediated toxicity is possible once the mechanism of toxicity has been elucidated.
77 citations
TL;DR: The results indicate that at concentrations of carbamazepine which produce marked induction of hepatic CYP3A, an enzyme involved in the metabolism and bioactivation of carbazepine, there is only a slight increase in lymphocyte microsomal epoxide hydrolase.
Abstract: 1. In order to determine whether carbamazepine is an inducer of lymphocyte microsomal epoxide hydrolase, the activity of the enzyme has been measured in the lymphocytes of 40 patients on continuous drug therapy using [3H]-cis stilbene oxide as a substrate. 2. Induction of the cytochrome P450 isoform, CYP3A, has been assessed in the same patients by measurement of the 24 h urinary excretion of 6 beta-hydroxycortisol by radioimmunoassay. The urinary concentrations of carbamazepine and its two metabolites, the 10,11-epoxide and trans-dihydrodiol, have also been measured by h.p.l.c. 3. The 24 h urinary 6 beta-hydroxycortisol excretion in the patients increased with the dose of carbamazepine (r = 0.57, P < 0.001) indicating induction of CYP3A. 4. The total amount of trans-dihydrodiol excreted in the urine increased with the dose of carbamazepine, and it was the most abundant urinary metabolite in all patients and at all dose-levels. There was no relationship between the dose of carbamazepine and the diol to epoxide ratio (r = 0.01, NS). 5. Lymphocyte microsomal epoxide hydrolase activity was marginally, but significantly (P = 0.02) higher in the patients (28.4 pmol diol min-1 mg-1 protein) than in drug-free controls (23.4 pmol diol min-1 mg-1 protein (95% CI for difference -9 to -0.8)). 6. The results indicate that at concentrations of carbamazepine which produce marked induction of hepatic CYP3A, an enzyme involved in the metabolism and bioactivation of carbamazepine, there is only a slight increase in lymphocyte microsomal epoxide hydrolase.
23 citations
TL;DR: In vitro techniques that incorporate human cells for the detection and characterization of stable, chemically reactive and cytotoxic metabolites are developed and their relevance to drug toxicity observed in humans will be illustrated by reference to studies with anticonvulsants and antimalarials.
18 citations
TL;DR: The oxidative metabolism of 2- and 4-BrEE2 in rats was sexually differentiated and 2-ClEE2 formed much less alkyl monohydroxylated metabolite than did either 2- BrEE2 or 2-IEE2, and all three of the C-2 halogenated derivatives were substantially excreted unchanged except for conjugation.
3 citations