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 virus type 1 (HIV-1) protease. This lipophilic compound was successfully entrapped into poly(D,L-lactic acid) (PLA) and pH sensitive methacrylic acid copolymers nanoparticle. The intravenous administration to mice of PLA nanoparticles loaded with CGP 57813 resulted in a 2-fold increase 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 solution. Following oral administration, only nanoparticles made of the methacrylic acid copolymer soluble at low pH provided sufficient plasma levels of CGP 57813. In vitro, these nanoparticles dissolved completely within 5 min at pH 5.8. PLA nanoparticles, which are insoluble in the gastrointestinal tract, did not provide significant plasma concentrations of CGP 57813. From these observations, one can conclude that the passage of intact PLA nanoparticles across the gastrointestinal mucosa appears to be very low.
Leroux
J C
JC
School of Pharmacy, University of Geneva, Switzerland.
Cozens
R
R
Roesel
J L
JL
Galli
B
B
Kubel
F
F
Doelker
E
E
Gurny
R
R
D000180:Acrylic Resins / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002219:Carbamates / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D016503:Drug Delivery Systems; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006207:Half-Life; D007275:Injections, Intravenous; D007773:Lactates; D019344:Lactic Acid; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011091:Polyesters; D011108:Polymers; D011109:Polymethacrylic Acids / Q000737:chemistry
D000180:Acrylic Resins; D002219:Carbamates; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D017320:HIV Protease Inhibitors; D007773:Lactates; D009842:Oligopeptides; D011091:Polyesters; D011108:Polymers; D011109:Polymethacrylic Acids; C098598:CGP 57813; C038300:methylmethacrylate-methacrylic acid copolymer; D019344:Lactic Acid; C033616:poly(lactide)