Abstract

The purpose of this study was to determine the potency and selectivity of the alpha-1 adrenergic receptor antagonist terazosin based on relationships 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 evaluated 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. Blockade effects and plasma concentrations were evaluated at selected times for periods of ≤24 hr. Terazosin produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against terazosin plasma concentration, direct relationships were observed that were well described by the sigmoidal maximal effect model and resulted in IUP and MAP IC₅₀ values of 48.6 and 12.2 ng/ml, respectively. Repeated daily dosing resulted in little accumulation of terazosin in plasma and demonstrated consistent blockade responses over 7 days. MAP blockade was observed up to 23 hr after terazosin administration, whereas IUP blockade returned to control levels before 23 hr. Combined pharmacokinetic/pharmacodynamic analysis showed no selective antagonism of IUP by terazosin but may provide a useful way to show uroselectivity of novel agents.