Document 0508
 DOCN  M9620508
 TI    Weak binding of VX-478 to human plasma proteins and implications for
       anti-human immunodeficiency virus therapy.
 DT    9602
 AU    Livington DJ; Pazhanisamy S; Porter DJ; Partaledis JA; Tung RD; Painter
       GR; Vertex Pharmaceuticals Inc., Cambridge, MA 02139, USA.
 SO    J Infect Dis. 1995 Nov;172(5):1238-45. Unique Identifier : AIDSLINE
       MED/96036379
 AB    VX-478 is a potent inhibitor of human immunodeficiency virus type 1
       (HIV-1) protease (Ki, 0.6 nM) and of HIV-1 replication in antiviral
       assays (IC90, 80 nM). The fractional binding of VX-478 to human plasma
       and to purified plasma proteins was determined by equilibrium dialysis
       and difference UV spectrophotometry. Binding to alpha 1-acid
       glycoprotein (89% at 2 microM total drug concentration, Kd of 4 microM)
       accounts for its fractional binding in plasma (93%). Stopped-flow
       spectrophotometry methods showed that binding is a reversible two-step
       process. The measured dissociation rate constant approaches 100 s-1. The
       antiviral effect of VX-478 was determined in the presence of 45% human
       plasma, in which the IC90 increased by 1.5-fold compared with control
       experiments in the presence of 15% fetal bovine serum. The effects of
       protein binding on the antiviral activity of VX-478 are minor, as
       expected for a weak drug-protein interaction.
 DE    Acquired Immunodeficiency Syndrome/*DRUG THERAPY  Animal  Antiviral
       Agents/*BLOOD  Blood  Blood Proteins/*METABOLISM  Cattle  Fetus  Human
       HIV Protease Inhibitors/*BLOOD  Kinetics  Molecular Structure
       Orosomucoid/*METABOLISM  Protein Binding  Spectrophotometry, Ultraviolet
       Sulfonamides/*BLOOD  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).