title: Reduction of the in vitro activity of A77003, an inhibitor of human immunodeficiency virus protease, by human serum alpha 1 acid glycoprotein.
abstract: Since plasma protein binding of antiinfectives can adversely affect drug activity, the effect of serum proteins on the in vitro antiviral activity of A77003, a human immunodeficiency virus type 1 (HIV) protease inhibitor, was investigated. In vitro, A77003 is effective in both acute and chronic infection in 10% fetal bovine or human serum. As the concentration of human serum was increased to 50%, antiviral efficacy decreased 3- to 6-fold. Purified human alpha 1 acid glycoprotein (alpha 1-AGP) at physiologic concentrations (0.5-2 mg/mL) dose-dependently reduced the antiviral activity of A77003. alpha 1-AGP at 1 mg/mL also antagonized the anti-HIV activity of A77003-zidovudine combinations. Therefore, higher concentrations of HIV protease inhibitors than would be predicted, on the basis of in vitro activity in the absence of physiologic concentrations of binding protein, may be required to effectively limit viral replication in vivo.
authors.affiliation: Department of Medicine, Albany Medical College, New York 12208.
authors.forename: J A
authors.initials: JA
authors.lastname: Bilello
authors.forename: P A
authors.initials: PA
authors.lastname: Bilello
authors.forename: M
authors.initials: M
authors.lastname: Prichard
authors.forename: T
authors.initials: T
authors.lastname: Robins
authors.forename: G L
authors.initials: GL
authors.lastname: Drusano
mesh_terms: D000998:Antiviral Agents / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D017320:HIV Protease Inhibitors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008782:Methylurea Compounds; D009961:Orosomucoid / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011725:Pyridines; D014633:Valine / Q000031:analogs & derivatives; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D008782:Methylurea Compounds; D009961:Orosomucoid; D011725:Pyridines; D015215:Zidovudine; C079555:Abbott 77003; D014633:Valine