Biotransformation of medetomidine in the rat

Abstract

1. The metabolites of a novel alpha 2-adrenoceptor agonist, medetomidine, in rat urine after subcutaneous administration at two dose levels (80 micrograms/kg or 5 mg/kg), and after incubation with rat liver fractions, were characterized by h.p.l.c., 1H-n.m.r and mass spectrometry. 2. Hydroxylation of a methyl substituent was the main biotransformation in vitro. Hydroxylation occurred at a rate sufficient for high metabolic clearance. 3. The major urinary metabolites were the glucuronide of hydroxymedetomidine (about 35% of urinary metabolites) and medetomidine carboxylic acid (about 40%). 4. Medetomidine unchanged represented about 1% or 10% of the urinary excretion products, dependent on dose. 5. A metabolic pathway consisting of hydroxylation with subsequent glucuronidation, or further oxidation to carboxylic acid, is suggested.

Pharmacokinetics and pharmacodynamics of intravenous medetomidine in the horse

“…2000). Metabolism of medetomidine involves hepatic biotransformation to the major metabolite, 3‐hydroxy‐medetomidine, and minor metabolites, carboxylic acid medetomidine and a glucuronide conjugate (Salonen & Eloranta 1990). The drug exhibits clinically desirable characteristics, such as dose dependent sedation and analgesia which is used in horses to provide sedation for standing procedures, prior to induction of anesthesia and as a component of anesthetic maintenance techniques.…”

Determination of Dexmedetomidine in Rat Plasma by a Sensitive [3H]Clonidine Radioreceptor Assay

“…However, it is known that the major metabolites of dexmedetomidine are devoid of affinity to the R-2 adrenergic receptor. 6 Endogenous compounds like (nor)epinephrine can easily be eliminated by choosing appropriate sample handling conditions. Previously, rat cortex has been used as the source of R-2 adrenergic receptors.…”

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).…”