A PHARMACOKINETIC-PHARMACODYNAMIC LINKING MODEL FOR THE ALPHA(2)-ADRENERGIC ANTAGONISM OF IDAZOXAN ON CLONIDINE-INDUCED MYDRIASIS IN THE RAT

The relationship between concentration and inhibitory effect of the al pha(2)-adrenoceptor antagonist idazoxan on clonidine-induced mydriasis has been studied in the rat using pharmacokinetic-pharmacodynamic sim ultaneous modelling. Fifteen minutes after the anaesthesia of rats wit h sodium pentobarbitone (55 mg kg(-1), i.p.), and 5 min after the admi nistration 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 differ ent time intervals, pupil diameters were assessed. The pharmacokinetic s of idazoxan were adequately described by a monoexponential equation. Using a pharmacokinetic-pharmacodynamic linking model, the concentrat ion-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, vol ume 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 co ntribute to better characterization of the pharmacodynamic and toxicol ogical profiles of idazoxan in experimental models in which a differen t pharmacokinetic behaviour of the drug is presumed.