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

Purpose. To evaluate regional intestinal absorption and the feasibilit y of sustained release dosage form development for an HIV protease inh ibitor, L-735,524. Methods. L-735,524 free base or sulfate salt was ad ministered 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 asses s plasma concentration profiles. In addition, drug was administered di rectly into the jejunum or colon of animals, and drug concentrations d etermined in portal circulation to characterize absorption from these sites. Results, L-735,524 sulfate was well absorbed orally from a solu tion or capsule formulation if fasted animals' stomachs were preacidif ied with citric acid solution. A free base suspension, delivered in di vided 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 concentrati ons 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 g avage. The free base suspension (pH 6.5) delivered into jejunal or col onic regions did not produce measurable systemic plasma concentrations . Conclusions. Extended release formulations did not prolong absorptio n of L-735,524 in dogs. Optimal L-735,524 absorption was dependent on solubility in an acidic environment in the duodenum.