title: Investigation of oral bioavailability and brain distribution of the Ind(8)-Val conjugate of indinavir in rodents.
abstract: Protease inhibitors are successfully used for the treatment of acquired immune deficiency syndrome (AIDS) although their biopharmaceutical characteristics are not optimal. Prodrugs have therefore been synthesized to increase protease inhibitor bioavailability and brain distribution. Among several compounds tested, a valine derivative of indinavir (Ind(8)-Val) showed promising characteristics using an in-vitro Caco-2 cell model. The objective of this study was to further investigate this compound using in-situ and in-vivo approaches. The pharmacokinetics of indinavir (Ind) and Ind(8)-Val were investigated in rats after intravenous and oral administration. Free indinavir resulting from in-vivo hydrolysis of Ind(8)-Val could not be detected in the plasma of rats receiving Ind(8)-Val. Furthermore Ind(8)-Val bioavailability was only 32% on average compared with 76% for indinavir, and effective permeability coefficients determined with a single-pass intestinal perfusion method were close to 25x10(6)cms(-1) for the two compounds. Brain-to-plasma concentration ratios in the post equilibrium phase after intravenous administration to mice were 9.7+/-8.1% for indinavir and 2.5+/-2.7% for Ind(8)-Val. In conclusion, the promising biopharmaceutical characteristics of Ind(8)-Val suggested from previous in-vitro experiments with the Caco-2 cell model were not confirmed by in-situ and in-vivo experiments.
authors.affiliation: EA3809 Pharmacologie des Agents Anti-Infectieux, Faculté de Médecine & Pharmacie, 86005 Poitiers Cedex, France.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pereira de Oliveira
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Olivier
authors.forename: Claudine
authors.initials: C
authors.lastname: Pariat
authors.forename: Dominique
authors.initials: D
authors.lastname: Roche
authors.forename: Jacques
authors.initials: J
authors.lastname: Greiner
authors.forename: Pierre
authors.initials: P
authors.lastname: Vierling
authors.forename: William
authors.initials: W
authors.lastname: Couet
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D019469:Indinavir / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007583:Jejunum / Q000378:metabolism; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D017320:HIV Protease Inhibitors; D011355:Prodrugs; D019469:Indinavir; D014633:Valine