Influence of the injection volume on the release pattern of intramuscularly administered propranolol to rats

Abstract

The aim of this study was to investigate the relationship between the injection volume and the bioavailability of propranolol after i.m. administration. Aqueous solutions of propranolol (3 mg) were administered i.m. in 50, 100 or 200 μl and i.v. (1 mg) in 0.5 ml to rats. Intramuscular injections were given alternately into the left and right hind leg. Blood samples were taken at regular time intervals during a period of 24 h. Propranolol concentrations in plasma were determined by HPLC. Intravenous data were fitted according to either a mono- or a bi-exponential function. The amount of non-absorbed drug remaining at the i.m. injection site was calculated according to the method of deconvolution. Absorption rate constants ( k a ) were calculated from the initial phases (0–90 min) of the log fraction of drug not-adsorbed vs time curves. The area under the curve (AUC 0− t ) to 8 h post-injection was calculated by the linear trapezoidal rule. A Kendall's rank order test ( α = 0.05) was applied for correlation testing. Intramuscular data showed a biphasic decline of propranolol in the blood; at early times the curves were steep while at later times they became flatter. Mean initial absorption rate constants (± S.D) were 0.12 (± 0.02), 0.20 (± 0.04) and 0.27 (± 0.07) h −1 respectively, and mean AUC 0− t per g body weight (± S.D.) after i.m. injection of 50, 100 and 200 μl were 5.3 (± 1.2), 7.0 (± 1.1) and 9.2 (± 1.8) μg h 1 −1, respectively. Propranolol availability after intramuscular injection was incomplete. A positive correlation between either AUC 0− t, or k a and the injection volume was established. An increased absorption rate at large injection volumes was shown not to be in accordance with the diffusion-controlled absorption model. This, and the incomplete release after 8 h, could be attributed to the precipitation at or binding of the drug to the injection site. It is concluded that the absorption rate as well as the availability of intramuscularly injected propranolol from aqueous solutions is influenced by the injection volume.