Comparative bioavailability of L-683,453, a 5α-reductase inhibitor, from a self-emulsifying drug delivery system in Beagle dogs

Bioavailabilities (BA) of the lipophilic compound, L-683,453, from several formulations were determined in fasted and fed purpose-bred Beagle dogs following oral administration and an i.v. reference dose. The compound is poorly soluble in water (∼0.001 mg/mL) and exhibited very low BA, 0.2%, from suspensions in methyl cellulose, in fasted dogs. Addition of sodium dodecyl sulfate (SDS) into suspensions increased BA significantly to 0.6% in fasted (P = 0.05) and to 1.7% in fed animals (P < 0.01). A more dramatic enhancement in BA, up to 13.7%, was achieved from a self-emulsifying formulation composed of mono- and di-glycerides of caprylic/capric acids (MDG) and surfactants. It was found that tolerability and efficacy of MDG-based formulations at 16 mg/kg depend not only on the dose but also on the dosing volume. A volume of 2 mL/kg caused emesis, while a volume of 1 mL/kg was well tolerated. In contrast to its effect on suspensions, food had no statistically significant effect on BA of self-emulsifying formulations at dosing volumes of 1 mL/kg and 0.25 mL/kg. However, peak plasma concentrations were achieved faster in fed than in fasted animals.