RELATIONSHIPS BETWEEN PHARMACOKINETICS AND BLOCKADE OF AGONIST-INDUCED PROSTATIC INTRAURETHRAL PRESSURE AND MEAN ARTERIAL-PRESSURE IN THE CONSCIOUS DOG AFTER SINGLE AND REPEATED DAILY ORAL-ADMINISTRATION OF TERAZOSIN

The purpose of this study was to determine the potency and selectivity of the alpha-1 adrenergic receptor antagonist terazosin based on rela tionships between plasma concentrations and blockade of intraurethral pressure (IUP) and mean arterial pressure (MAP) responses after single dosing and to determine cumulative effects after repeated dosing. To this end, the relationships between plasma concentrations and blockade effects of terazosin on phenylephrine (PE)-induced IUP and MAP were e valuated in conscious male beagle dogs after single (0.1, 0.3 and 1 mg /kg) and repeated (0.3 and 1 mg/kg) daily oral dosing of terazosin, Bl ockade effects and plasma concentrations were evaluated at selected ti mes for periods of less than or equal to 24 hr. Terazosin produced dos e-dependent antagonism of PE-induced IUP and MAP responses, When IUP a nd MAP blockade effects were plotted against terazosin plasma concentr ation, direct relationships were observed that were well described by the sigmoidal maximal effect model and resulted in IUP and MAP IC50 va lues of 48.6 and 12.2 ng/ml, respectively, Repeated daily dosing resul ted in little accumulation of terazosin in plasma and demonstrated con sistent blockade responses over 7 days, MAP blockade was observed up t o 23 hr after terazosin administration, whereas IUP blockade returned to control levels before 23 hr. Combined pharmacokinetic/pharmacodynam ic analysis showed no selective antagonism of IUP by terazosin but may provide a useful way to show uroselectivity of novel agents.