Characterization of brimonidine metabolism with rat, rabbit, dog, monkey and human liver fractions and rabbit liver aldehyde oxidase
| Autor: | Diane D.-S. Tang-Liu, Nguyen H, Stephen A. Munk, Michael E. Garst, Harcourt Dale A, Lam S, Andrew Acheampong, Chien Ds, Breau A, Vekich S, Usansky J |
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| Rok vydání: | 1996 |
| Předmět: |
Adult
Male Health Toxicology and Mutagenesis Urinary system Urine Biology Acetates Toxicology Biochemistry Aldehyde Guanidines Mass Spectrometry chemistry.chemical_compound Dogs Menadione Species Specificity Quinoxalines medicine Animals Humans Aldehyde oxidase Guanidine Pharmacology chemistry.chemical_classification Brimonidine General Medicine Metabolism Haplorhini Aldehyde Oxidoreductases Rats Aldehyde Oxidase S9 fraction chemistry Liver Brimonidine Tartrate Rabbits medicine.drug Chromatography Liquid |
| Zdroj: | Xenobiotica; the fate of foreign compounds in biological systems. 26(10) |
| ISSN: | 0049-8254 |
| Popis: | 1. In vitro metabolism of 14C-brimonidine by the rat, rabbit, dog, monkey and human liver fractions was studied to assess any species differences. In vitro metabolism with rabbit liver aldehyde oxidase and human liver slices, and in vivo metabolism in rats were also investigated. The hepatic and urinary metabolites were characterized by liquid chromatography and mass spectrometry. 2. Up to seven, six, 11 and 14 metabolites were detected in rat liver S9 fraction, human liver S9 fraction, human liver slices and rat urine respectively. Rabbit liver aldehyde oxidase catalysed the metabolism of brimonidine to 2-oxobrimonidine and 3-oxobrimonidine, and further oxidation to the 2,3-dioxobrimonidine. Menadione inhibited the liver aldehyde oxidase-mediated oxidation. 3. Hepatic oxidation of brimonidine to 2-oxobrimonidine, 3-oxobrimonidine and 2,3-dioxobrimonidine was a major pathway in all the species studied, except the dog whose prominent metabolites were 4',5'-dehydrobrimonidine and 5-bromo-6-guanidinoquinoxaline. 4. These results indicate extensive hepatic metabolism of brimonidine and provide evidence for aldehyde oxidase involvement in brimonidine metabolism. The species differences in hepatic brimonidine metabolism are likely related to the low activity of dog liver aldehyde oxidase. The principal metabolic pathways of brimonidine are alpha(N)-oxidation to the 2,3-dioxobrimonidine, and oxidative cleavage of the imidazoline ring to 5-bromo-6-guanidinoquinoxaline. |
| Databáze: | OpenAIRE |
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