Metabolism of detomidine in the rat II. Characterisation of metabolites in urine

Abstract

In order to investigate the biotransformation of a new alpha 2-adrenoceptor agonist, detomidine, metabolites were isolated from rat urine by solid phase extraction and purified by TLC. The isolated compounds were structurally analysed by 1H-NMR, MS and GC-MS as such or as their methyl and/or silyl derivatives. In addition to detomidine, which was found in trace amounts, four major metabolites were identified: hydroxymethyldetomidine, the corresponding O-glucuronide, detomidine carboxylic acid, and detomidine mercapturate. Together the identified components make up about 80% of urinary detomidine derived compounds. On the basis of these findings a major biotransformation pathway could be suggested. The reaction sequence is initiated by a hydroxylation. Subsequent glucuronidation, glutathione conjugation or secondary oxidation divide the route into three branches each producing one of the other three identified metabolites.

Pharmacokinetics of detomidine and its metabolites following intravenous and intramuscular administration in horses

“…This was to be expected as the biotransformation of detomidine involves an aliphatic hydroxylation of detomidine to generate OH-detomidine. The OH-detomidine undergoes a further dehydrogenation reaction to generate COOH-detomidine (Salonen et al 1988).…”

N-Glucuronidation of Some 4-Arylalkyl-1H-Imidazoles by Rat, Dog, and Human Liver Microsomes

“…Dexmedetomidine (Precedex; Abbott Laboratories, Abbott Park, IL) was recently approved for clinical use for sedation of patients in intensive care. Biotransformation is the most important pathway in the elimination of these compounds (Salonen et al, 1988(Salonen et al, , 1991Salonen and Eloranta, 1990). When the metabolism of levomedetomidine was first studied in human liver microsomes, direct glucuronidation to the imidazole ring nitrogen was observed (Lehtonen and Salonen, 1997).…”

Identification of detomidine carboxylic acid as the major urinary metabolite of detomidine in the horse

“…N-hydroxydetomidine could also be regarded as the unknown immunoreactive metabolite previously found in horse and cattle urine (2,10). In this molecule, the aromatic part needed for recognition by detomidine antiserum has remained intact Also the concentration ranges reported for the immunoreactivity and found for the suggested N-hydroxy metabolite are the same.…”

“…Detomidine is a potent centrally acting drug whose effects in the animal are terminated by metabolic elimination of the compound (1). In the rat, its biotransformation occurs by oxidation and subsequent conjugation into the arylalkyl moiety of the molecule (2). No data on the biotransformation of detomidine or related arylalkylimidazoles in the horse have been published.…”