Relationship between plasma prazosin concentrations and α‐antagonism in humans: Comparison of conventional and rate‐controlled (Oros) formulations

A single‐dose comparative evaluation in young normotensive men of the plasma concentrations and α‐adrenoceptor antagonism after conventional prazosin and a new slow‐release formulation (Oros) is described. Whereas conventional prazosin (2 mg) produced a maximum reduction in erect blood pressure at 3 hours (80/46 mm Hg compared with 110/65 mm Hg with placebo), the lowest blood pressure of 94/48 mm Hg with Oros prazosin (5.5 mg) was not observed until 8 hours after administration. Twenty‐four hours after Oros prazosin, prazosin was still detectable in plasma and erect blood pressure was reduced to 107/58 mm Hg compared with 110/71 mm Hg after placebo. α 1 ‐Antagonism (assessed by the pressor responses to intravenous phenylephrine) was maximal, with a 4.8‐fold shift in dose‐response 24 hours after Oros prazosin, and persisted at least until 30 hours after administration, with a 2.3‐fold shift. There were significant correlations between α 1 ‐antagonism and plasma prazosin concentrations for both Oros and conventional prazosin. The slopes of these relationships were significantly different, but this is thought to be consistent with the differences in the rates of drug release from the two formulations. Overall this study provides further evidence in humans that the duration and extent of the α 1 ‐antagonism and the blood pressure response reflect the plasma prazosin concentrations. Additionally these data suggest the potential suitability of this type of a slow‐release formulation for single daily administration. Clinical Pharmacology and Therapeutics (1988) 43, 582–587; doi: 10.1038/clpt.1988.77