THE BIOAVAILABILITY OF ORAL DOSAGE FORMS OF A NEW HIV-1 PROTEASE INHIBITOR, KNI-272, IN BEAGLE DOGS

The bioavailability (BA) of a tripeptide protease inhibitor, KNI-272, which has a strong pharmacological potential for treating human immuno deficiency virus type 1 (HIV-1), has been studied in beagle dogs by ad ministering several oral dosage forms. The tested dosage forms were fo rm 1, plain gelatin capsules; forms 2 and 3, gelatin capsules of which the inner and outer surfaces were coated with 7G ethylcellulose (EC, 30 mu m thickness) and an enteric coating material, hydroxypropyl meth ylcellulose phthalate (HP-55), respectively; and form 4, gelatin capsu les of which the inner surface is coated with 10G EC (60 mu m thicknes s). The difference between forms 2 and 3 was the amount of citric acid contained in the capsule, namely 100 mg in form 2 and 200 mg in form 3. One hundred milligrams of KNI-272 was placed in each capsule after being dissolved with propylene glycol (PG). These capsules were used t o deliver KNI-272 to the stomach for form I, to the upper part of the small intestine for forms 2 and 3, and to the middle part of the small intestine for form 4. As a reference, 50.0 mg of KNI-272 was administ ered to the same dogs by intravenous (IV) infusion for 15 min. By meas uring the plasma drug levels with the HPLC method, BAs were estimated for each test dosage form. Form 1 showed the highest BA of 26.2+/-7.0% (mean+/-SE), though the other capsules showed BAs of approximately 10 %, namely 6.6+/-0.4% for form 2, 10.3+/-1.1% for form 3 and 14.2+/-1.0 % for form 4. Therefore, as the site where KNI-272 is released from th e capsule becomes higher, the BA increases. In addition, as the amount of citric acid contained in a capsule increases, the BA value tends t o increase. These results suggest that KNI-272 is stable and not exten sively hydrolysed in the gut after oral administration, that the disso lution process into GI fluids is important for the BA of KNI-272, and that the most appropriate absorption site of KNI-272 in dogs is the du odenum. The potential of this new tripeptide compound as an orally act ive anti-AIDS drug has been confirmed.