Sustained Absorption does not Necessarily Reduce the Systemic Availability of Propranolol

Abstract

The in vitro dissolution and in vivo pharmacokinetics of two marketed long-acting propranolol formulations, Duranol (D) and Inderal LA (LA) were examined. Dissolution rates were obtained using the USP rotating basket method, while the relative bioavailabilities of the products were evaluated in normal volunteers under single-dose (6 subjects) and steady-state (11 subjects) conditions in two separate crossover studies. Both LA and D demonstrated pH-independent dissolution profiles with T₅₀ values of 4 and 6 hours, respectively. While the dissolution profile for D was sigmoidal and complete in 12 hours, data for LA suggested a log-linear profile and indicated only 85% dissolution at 12 hours. In pharmacokinetic studies the tmax was achieved in 7 to 8 hours for both products; however, Cmax values for D vs LA were 80.4 vs 49.9 ng/ml (p < 0.05) after a single dose and 76.6 vs 52.6 ng/ml (p < 0.01) at steady-state drug administration. The bioavailability of D was 55% and 44% greater than that of LA during single-dose and steady-state studies, respectively. Intersubject variability was lower for D than for LA during both studies. The data indicate that sustained absorption does not necessarily reduce the systemic availability of propranolol, and suggest that formulation-related factors may contribute to the low bioavailability of LA. The superior bioavailability and lower intersubject variability achieved with D compared to LA suggest that D should be at least as effective as LA in the treatment of cardiovascular disorders.