CHARACTERIZATION OF BRIMONIDINE METABOLISM WITH RAT, RABBIT, DOG, MONKEY AND HUMAN LIVER FRACTIONS AND RABBIT LIVER ALDEHYDE OXIDASE

1. In vitro metabolism of C-14-brimonidine by the rat, rabbit, dog, mo nkey and human liver fractions was studied to assess any species diffe rences. In vitro metabolism with rabbit liver aldehyde oxidase and hum an liver slices, and in vivo metabolism in rats were also investigated . The hepatic and urinary metabolites were characterized by liquid chr omatography and mass spectrometry. 2. Up to seven, six, 11 and 14 meta bolites were detected in rat liver S9 fraction, human liver S9 fractio n, human liver slices and rat urine respectively. Rabbit liver aldehyd e oxidase catalysed the metabolism of brimonidine to 2-oxobrimonidine and 3-oxobrimonidine, and further oxidation to the 2,3-dioxobrimonidin e. Menadione inhibited the liver aldehyde oxidase-mediated oxidation. 3. Hepatic oxidation of brimonidine to 2-oxobrimonidine, 2-oxobrimonid ine and 2,3-dioxobrimonidine was a major pathway in all the species st udied, except the dog whose prominent metabolites were 4',5'-dehydrobr imonidine and 5-bromo-6-guanidinoquinoxaline. 4. These results indicat e extensive hepatic metabolism of brimonidine and provide evidence for aldehyde oxidase involvement in brimonidine metabolism. The species d ifferences in hepatic brimonidine metabolism are likely related to the low activity of dog liver aldehyde oxidase. The principal metabolic p athways of brimonidine are alpha(N)-oxidation to the 2,3-dioxobrimonid ine, and oxidative cleavage of the imidazoline ring to 5-bromo-6-guani dinoquinoxaline .