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 alpha 2-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-pharmaco-dynamic linking model, the concentration-effect relationships of idazoxan were derived, and were quantified by the inhibitory simple Emax 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.
Valles
J
J
Department of Pharmacology and Psychiatry, School of Medicine, Universitat Autònoma de Barcelona, Spain.
Obach
R
R
Menargues
A
A
Pruñonosa
J
J
Jane
F
F
D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003000:Clonidine / Q000008:administration & dosage / Q000633:toxicity*; D003198:Computer Simulation; D004146:Dioxanes / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D019329:Idazoxan; D007275:Injections, Intravenous; D008297:Male; D008956:Models, Chemical; D015878:Mydriasis / Q000139:chemically induced / Q000188:drug therapy*; D011680:Pupil / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D003000:Clonidine; D019329:Idazoxan