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

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.