Tissue‐Specificity of Hydroxylation and N‐Methylation of Arylalkylimidazoles

Abstract

Hydroxylation and N-methylation of three potent alpha 2-adrenoceptor agonists detomidine, medetomidine and dexmedetomidine by rat brain, kidney, liver and lung were studied in vitro. NADPH-dependent hydroxylation of the 3'-methyl group was catalyzed mainly by the microsomal fraction of liver. Monooxygenation by the other tissues was negligible. The hepatic monooxygenase reaction was characterized by high affinity (Km 5.5-9.8 microM) and low capacity (Vmax 29-66 pmol/min. per mg protein). Statistically significant (P less than 0.05) differences between the Km and Vmax values of medetomidine and dexmedetomidine were observed suggesting stereoselective oxidation of the drug molecule. N-Methylation of the arylalkylimidazoles occurred mainly in the cytosolic fraction of the kidney. With S-adenosylmethionine as the methyl donor, the transferase activities in other tissues were less than 10% of the specific activity of the renal enzyme (about 7 pmol/min. per mg protein for medetomidine). Even the renal enzyme showed a relatively low capacity (Km 250-300 microM and Vmax 15-33 pmol/min. per mg protein). Different tissue distributions of the arylalkylimidazole N-methyltransferase and histamine N-methyltransferase suggest that they are two distinct enzyme species. Based on these results, aliphatic hydroxylation is the major (metabolic) elimination mechanism of the arylalkylimidazole drugs, and liver is the principal eliminating organ. The importance of N-methylation is diminished by its low capacity and probable regeneration of the parent drug by demethylation.

Hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats

“…A single dose pharmacokinetic study may therefore not allow adequate characterization of the disposition of the drug over a wide dose range. Hydroxylation in the liver has been reported to be the main pathway for dexmedetomidine elimination (Salonen 1991), and it is likely that liver blood flow decreases following administration of this drug (Lawrence et al. 1996).…”

Effect of dexmedetomidine on the minimum alveolar concentration of isoflurane in cats

“…A single dose pharmacokinetic study may therefore not allow adequate characterization of the disposition of the drug over a wide dose range. Hydroxylation in the liver has been reported to be the main pathway for dexmedetomidine elimination (Salonen, 1991), and it is likely that liver blood flow decreases following administration of this drug (Lawrence et al, 1996). The effect of dexmedetomidine-induced decrease in cardiac output on its pharmacokinetics has been reported in humans (Dutta et al, 2000).…”

Dexmedetomidine Combined with Therapeutic Hypothermia Is Associated with Cardiovascular Instability and Neurotoxicity in a Piglet Model of Perinatal Asphyxia

“…Isoflurane-anaesthetized dogs and cats developed greater negative cardiovascular effects with dexmedetomidine as an adjunct compared to isoflurane-only anaesthesia [52,53]. Dexmedetomidine reduces cardiac output, and the subsequent redistribution of blood flow limits hepatic and other non-vital organ perfusion [54] ; this, in turn, reduces the hepatic blood flow and hydroxylation and clearance [55,56] . In our piglets, it is likely that the interaction between dexmedetomidine and isoflurane anaesthesia (the negative inotropic effect and vasodilation) are likely to have increased the depression of the sympathetic activity [57] by the variable binding to peripheral and central α 2 -adrenergic receptors [58] .…”