A Pharmacokinetic-pharmacodynamic Linking Model for the α2-Adrenergic Antagonism of Idazoxan on Clonidine-induced Mydriasis in the Rat

The relationship between concentration and inhibitory effect of the α₂-adrenoceptor antagonist idazoxan on clonidine-induced mydriasis has been studied in the rat using pharmacokinetic-pharmacodynamic simultaneous modelling. Fifteen minutes after the anaesthesia of rats with sodium pentobarbitone (55 mg kg-1, i.p.), and 5 min after the administration of clonidine (0·3 mg kg^?1, i.v.) to rats pretreated with idazoxan (3 mg kg^?1, i.v., and 3 and 10 mg kg^?1, orally) at different time intervals, pupil diameters were assessed. The pharmacokinetics of idazoxan were adequately described by a monoexponential equation. Using a pharmacokinetic-pharmacodynamic linking model, the concentration-effect relationships of idazoxan were derived, and were quantified by the inhibitory simple E_max model. At the effect compartment, the estimated apparent IC50 was 153·6 ng mL^?1. Values of clearance, volume of distribution and elimination half-life were 71·2 mL kg^?1 min^?1, 3134 mL kg^?1 and 30-5 min, respectively. These results could contribute to better characterization of the pharmacodynamic and toxicological profiles of idazoxan in experimental models in which a different pharmacokinetic behaviour of the drug is presumed.