Application of pharmacokinetic-pharmacodynamic modelling for the comparison of quinazoline alpha-adrenoceptor agonists in normotensive volunteers

• Published in: Journal of cardiovascular pharmacology Vol. 7; no. 3; p. 532
• Main Authors: Meredith, P A, Elliott, H L, Kelman, A W, Reid, J L
• Format: Journal Article
• Language: English
• Published: United States 01-05-1985
• Subjects: Adrenergic alpha-Agonists - blood; Adult; Blood Pressure - drug effects; Dose-Response Relationship, Drug; Doxazosin; Humans; Kinetics; Male; Mathematics; Piperazines - blood; Posture; Prazosin - analogs & derivatives; Prazosin - blood; Quinazolines - blood
• ISSN: 0160-2446
• DOI: 10.1097/00005344-198505000-00019

Prazosin, doxazosin, and trimazosin are structural analogues with relatively selective peripheral alpha 1-adrenoceptor antagonist properties. The relationships between the pharmacokinetics and pharmacodynamics for these three drugs have been studied following acute intravenous administration in normotensive subjects. The mean terminal elimination half-life (+/- SD) for prazosin was 2.0 +/- 0.4 h, and that for trimazosin was comparable at 3.1 +/- 0.3 h, whilst the mean terminal elimination half-life for doxazosin was significantly longer at 9.4 +/- 1.5 h. The clearance of prazosin (mean, 327 +/- 78 ml/min) was greater than that of both doxazosin (139 +/- 30 ml/min) and trimazosin (67 +/- 29 ml/min). The hypotensive effects of prazosin and doxazosin were fitted to an integrated pharmacokinetic-pharmacodynamic model with similar resulting values for the parameter describing responsiveness. The pharmacodynamic profile of trimazosin was subjected to similar analysis and was most appropriately fitted to a model incorporating an effect compartment associated with both parent drug and its major metabolite 1-hydroxy trimazosin.