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The mechanism of bioactivation and antigen formation of amodiaquine in the rat

Identifieur interne : 002E53 ( Main/Exploration ); précédent : 002E52; suivant : 002E54

The mechanism of bioactivation and antigen formation of amodiaquine in the rat

Auteurs : Anthony C. Harrison [Royaume-Uni] ; Neil R. Kitteringham [Royaume-Uni] ; Janet B. Clarke [Royaume-Uni] ; B. Kevin Park [Royaume-Uni]

Source :

Biochemical Pharmacology [ 0006-2952 ] ; 1992.

RBID : ISTEX:013DF7FF6FB0711322F42C55A138720CAB3258D6

English descriptors

Teeft :
- Adduct, Amodiaquine, Amodiaquine quinoneimine, Bile, Bile samples, Biliary, Chronic administration, Conjugation, Control rats, Cyclic voltammetry, Cysteine, Cysteine conjugate, Cytochrome, Desethylamodiaquine, Direct evidence, Drug metab dispos, Excretion, Flow rate, Glutathione, Glutathione adduct, Glutathione adducts, Glutathione conjugate, Hepatic, Hplc, Irreversible binding, Isomer, Ketoconazole, Liver homogenates, Liver tissue protein, Male wistar rats, Mass spectrometry, Mass spectrum, Metabolic activation, Metabolism, Metabolite, Methanol, Organic chemistry, Oxidation potentials, Parent drug, Positive mode, Quinoneimine, Radioactivity, Reactive, Reactive species, Sodium phosphate buffer, Spectrometry, Thioether conjugates, Unambiguous characterization.

Abstract

Abstract: A glutathione conjugate of amodiaquine has been isolated and characterized from rat bile after administration of [14C]amodiaquine (50 μmol/kg, 5.0 μCi/rat) to anaesthetized male Wistar rats. Thioether conjugates of amodiaquine in rat bile accounted for a total of 12% of the dose, 5 hr after administration of the drug. In addition, 1% of the dose remained in the liver covalently bound to tissue proteins after 5hr. These findings provide direct evidence that a chemically reactive metabolite, amodiaquine quinoneimine, has been formed from the drug in vivo. A second major metabolite, desethylamodiaquine, accounting for 14% of the given dose, was present in the liver after 5 hr. Enzyme inhibition studies with ketoconazole-pretreated rats showed that both amodiaquine quinoneimine and desethylamodiaquine formation can be catalysed by cytochrome P450. The demonstration that amodiaquine readily and extensively forms a metabolite in vivo, with strong reactivity towards protein and non-protein thiol groups, may help to explain the idiosyncratic toxicity observed in man.

Url:

https://api.istex.fr/ark:/67375/6H6-5VDJ1KSL-Z/fulltext.pdf

DOI: 10.1016/0006-2952(92)90198-R

Affiliations:

Royaume-Uni

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Le document en format XML

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<term>Bile samples</term>
<term>Biliary</term>
<term>Chronic administration</term>
<term>Conjugation</term>
<term>Control rats</term>
<term>Cyclic voltammetry</term>
<term>Cysteine</term>
<term>Cysteine conjugate</term>
<term>Cytochrome</term>
<term>Desethylamodiaquine</term>
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<term>Drug metab dispos</term>
<term>Excretion</term>
<term>Flow rate</term>
<term>Glutathione</term>
<term>Glutathione adduct</term>
<term>Glutathione adducts</term>
<term>Glutathione conjugate</term>
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<term>Hplc</term>
<term>Irreversible binding</term>
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<term>Ketoconazole</term>
<term>Liver homogenates</term>
<term>Liver tissue protein</term>
<term>Male wistar rats</term>
<term>Mass spectrometry</term>
<term>Mass spectrum</term>
<term>Metabolic activation</term>
<term>Metabolism</term>
<term>Metabolite</term>
<term>Methanol</term>
<term>Organic chemistry</term>
<term>Oxidation potentials</term>
<term>Parent drug</term>
<term>Positive mode</term>
<term>Quinoneimine</term>
<term>Radioactivity</term>
<term>Reactive</term>
<term>Reactive species</term>
<term>Sodium phosphate buffer</term>
<term>Spectrometry</term>
<term>Thioether conjugates</term>
<term>Unambiguous characterization</term>
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<front><div type="abstract" xml:lang="en">Abstract: A glutathione conjugate of amodiaquine has been isolated and characterized from rat bile after administration of [14C]amodiaquine (50 μmol/kg, 5.0 μCi/rat) to anaesthetized male Wistar rats. Thioether conjugates of amodiaquine in rat bile accounted for a total of 12% of the dose, 5 hr after administration of the drug. In addition, 1% of the dose remained in the liver covalently bound to tissue proteins after 5hr. These findings provide direct evidence that a chemically reactive metabolite, amodiaquine quinoneimine, has been formed from the drug in vivo. A second major metabolite, desethylamodiaquine, accounting for 14% of the given dose, was present in the liver after 5 hr. Enzyme inhibition studies with ketoconazole-pretreated rats showed that both amodiaquine quinoneimine and desethylamodiaquine formation can be catalysed by cytochrome P450. The demonstration that amodiaquine readily and extensively forms a metabolite in vivo, with strong reactivity towards protein and non-protein thiol groups, may help to explain the idiosyncratic toxicity observed in man.</div>
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The mechanism of bioactivation and antigen formation of amodiaquine in the rat

The mechanism of bioactivation and antigen formation of amodiaquine in the rat

Source :

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri