PHARMACOKINETICS OF A NOVEL HIV-1 PROTEASE INHIBITOR INCORPORATED INTO BIODEGRADABLE OR ENTERIC NANOPARTICLES FOLLOWING INTRAVENOUS AND ORAL-ADMINISTRATION TO MICE

CGP 57813 is a peptidomimetic inhibitor of human immunodeficiency viru s type 1 (HIV-1) protease. This lipophilic compound was successfully e ntrapped into poly(D,L-lactic acid) (PLA) and pH sensitive methacrylic acid copolymers nanoparticles. The intravenous administration to mice of PLA nanoparticles loaded with CGP 57813 resulted in a 2-fold incre ase of the area under the plasma concentration-time curve, compared to a control solution. An increase in the elimination half-life (from 13 to 61 min) and in the apparent volume of distribution (1.7-3.6 L/kg) was observed for the nanoparticle incorporated compound vs control sol ution. Following oral administration, only nanoparticles made of the m ethacrylic acid copolymer soluble at low pH provided sufficient plasma levels of CGP 57813. in vitro, these nanoparticles dissolved complete ly within 5 min at pH 5.8. PLA nanoparticles, which are insoluble in t he gastrointestinal tract, did not provide significant plasma concentr ations of CGP 57813. From these observations, one can conclude that th e passage of intact PLA nanoparticles across the gastrointestinal muco sa appears to be very low.