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 Emaxmodel. 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−1min−1, 3134 mL kg−1and 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. 1995 Royal Pharmaceutical Society of Great Britain