Atipamezole increases medetomidine clearance in the dog: an agonist—antagonist interaction

Abstract

Medetomidine, an alpha 2-adrenoceptor agonist, is a potent sedative and analgesic agent in the dog. When necessary, its action can be effectively antagonized by atipamezole. The present work was designed to study the effects of these drugs on each others' pharmacokinetics when a single intramuscular dose of medetomidine (50 micrograms kg-1) was followed by a dose of atipamezole (250 micrograms kg-1). Three different treatments were used: medetomidine alone, atipamezole alone, and atipamezole after medetomidine. Drug concentrations in plasma were measured by GC-MS. Statistical analysis of the results (ANOVA) revealed significant differences between treatments in the kinetic parameters of medetomidine. Atipamezole decreased the AUC of medetomidine from 41.3 to 28.6 ng h ml-1 (P = 0.005), t1/2 from 1.44 to 0.87 h (P = 0.015), and increased Cl from 21 to 31 ml min-1 kg-1 (P = 0.017). Differences in Vz did not reach statistical significance. The only statistically significant effects of medetomidine on the pharmacokinetics of atipamezole in this study were the slight decrease of Cl and Cmax as well as the increase of AUC. It is suggested that the large dose of medetomidine used caused haemodynamic changes, resulting in decreased hepatic circulation and slower drug metabolism. Antagonism by atipamezole restored the hepatic blood flow and, consequently, increased the elimination of medetomidine by biotransformation.

Influence of MK-467, a Peripherally Acting α2-Adrenoceptor Antagonist on the Disposition of Intravenous Dexmedetomidine in Dogs

“…In the present study, differences in both the systemic hemodynamic performance (i.e., distribution) and liver perfusion (i.e., clearance) might have then contemporaneously affected the plasma concentrations during the whole of the sampling period, especially because the differences in cardiac index between treatments remained obvious throughout . In fact, Salonen et al (1995) concluded that administration of atipamezole, a centrally and peripherally acting ␣ 2 -adrenoceptor antagonist, increased the clearance of racemic medetomidine in dogs by restoring hepatic blood flow. However, cardiac output or hepatic perfusion was not measured in their study.…”

“…Dexmedetomidine has also been shown to dose dependently reduce its own clearance in humans, a phenomenon mediated via reduced cardiac output (Dutta et al, 2000). Likewise, dexmedetomidine has been suggested to alter its own pharmacokinetics in dogs (Salonen et al, 1995;Kuusela et al, 2000). It also reduces the distribution of thiopental in humans (Bührer et al, 1994).…”

Actions and pharmacokinetic properties of the α2-adrenergic agents, medetomidine and atipamezole, in rainbow trout (Oncorhynchus mykiss)

“…and 72 min when administered with medctomidine. The pharmacokinetic properties of atipamezole were not studied separately and so the pharmacokinetic data reported here are likely to have been affected by medetomidine, as reported by Salonen et al (1995) and Ranheim et al ( 1997).…”

“…The elimination half-life of atipamezole in rainbow trout ( 5 16 min) is also considerably longer than in other animals: 60 rnin in reindeer (Ranheim el ul. 1997); 57 niin (when administered alone) in dogs (Salonen et al 1995). and 72 min when administered with medctomidine.…”

Repeated anaesthesia with isoflurane and medetomidine-midazolam-fentanyl in guinea pigs and its influence on physiological parameters

“…Apparently, MMF anaesthesia and AFN antagonization repetition intervals of 3 or 4 days pharmacologically affected the regulation of the RR, possibly through a faster biotransformation. Both medetomidine and atipamezole are metabolized by hydroxylation through the enzyme cytochrome P450 [13] and the repetitive administration may have caused this enzyme complex to be up-regulated. This hypothesis is supported by the comparatively large reduction step from round 1 to 2 and smaller effects with further rounds.…”