REGIOSPECIFIC INTESTINAL-ABSORPTION OF THE HIV PROTEASE INHIBITOR L-735,524 IN BEAGLE DOGS

Purpose. To evaluate regional intestinal absorption and the feasibility of sustained release dosage form development for an HIV protease inhibitor, L-735,524. Methods. L-735,524 free base or sulfate salt was administered orally as suspension, solution or in solid dosage forms to fasted or fed Beagle dogs. Delayed-release dosage forms with ''slow'' or ''fast'' in vitro dissolution rates were evaluated in vivo to assess plasma concentration profiles. In addition, drug was administered directly into the jejunum or colon of animals, and drug concentrations determined in portal circulation to characterize absorption from these sites. Results, L-735,524 sulfate was well absorbed orally from a solution or capsule formulation if fasted animals' stomachs were preacidified with citric acid solution. A free base suspension, delivered in divided doses to fed animals, was also well absorbed. Prototype extended release dosage forms of L-735,524 produced a reduction in peak plasma levels but failed to prolong absorption and extend plasma concentrations compared to an immediate release capsule. Administration of L-735,524 sulfate solution (pH<3) as bolus solution or by infusion into the jejunum resulted in rapid but incomplete absorption compared to oral gavage. The free base suspension (pH 6.5) delivered into jejunal or colonic regions did not produce measurable systemic plasma concentrations. Conclusions. Extended release formulations did not prolong absorption of L-735,524 in dogs. Optimal L-735,524 absorption was dependent on solubility in an acidic environment in the duodenum.