Metabolism of detomidine in the rat. I. Comparison of³H-labelled metabolites formed in vitro and in vivo

Summary

The biotransformation of detomidine, a new a₂-adrenoceptor agonist, was studied using rat as the model animal. In vivo metabolism of the tritiated drug was compared to in vitro incubations with liver homogenates and intact, isolated hepatocytes. Metabolites were analysed by HPLC with radioactivity detection.

The metabolic patterns in all systems were closely related. HPLC of urine gave twelve radioactive peaks. Tritiated water and unchanged³H-detomidine were minor components. The two major peaks were tentatively identified as hydroxylated detomidine (14%) and its O-glucuronide (43%). Sulphate conjugates were not found.

Isolated hepatocytes converted detomidine to the same two major products; the relative amount of the glucuronide increased with incubation time. In liver post-mitochondrial supernatant, hydroxylation was the dominant reaction, and the hydroxylated product comprised 74% of the total metabolites with non-induced and 50% with phenobarbital-induced liver.

The major biotransformation in rat was thus concluded to be hydroxylation by the liver monooxygenases followed by glucuronic acid conjugation. The maximal rate of oxidation or the enzymatic capacity of a whole liver was estimated to be at least 100 nmol/min allowing for a high hepatic extraction ratio for detomidine. Together with the effective excretion of the glucuronide, this reaction sequence alone could account for the rapid elimination of the drug.