Application of pharmacokinetic-pharmacodynamic modelling for the comparison of quinazoline alpha-adrenoceptor agonists in normotensive volunteers.
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.
P A
PA
Meredith
H L
HL
Elliott
A W
AW
Kelman
J L
JL
Reid
D000316:Adrenergic alpha-Agonists / Q000097:blood*; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D017292:Doxazosin; D006801:Humans; D007700:Kinetics; D008297:Male; D008433:Mathematics; D010879:Piperazines / Q000097:blood; D011187:Posture; D011224:Prazosin / Q000031:analogs & derivatives / Q000097:blood; D011799:Quinazolines / Q000097:blood*
D000316:Adrenergic alpha-Agonists; D010879:Piperazines; D011799:Quinazolines; C005185:trimazosin; C040290:1-hydroxytrimazosin; D017292:Doxazosin; D011224:Prazosin