title: Equilibrium distribution of HIV antiviral drugs into human peripheral blood mononuclear cells (PBMC) is controlled by free drug concentration in the extracellular medium.
abstract: Effect of protein binding on the equilibrium distribution of selected HIV antiviral drugs into isolated human peripheral blood mononuclear cells (PBMC, mainly lymphocytes) was investigated. Human PBMC from a single healthy human donor were isolated, purified, and cryopreserved. Uptake of non-peptide HIV-1 protease inhibitors PNU-96988 and PNU-103017 by these cells in vitro was evaluated as a function of increasing concentration of human serum in the cell incubation media. Both PNU-96988 and PNU-103017 were extensively bound to serum proteins. Uptake/efflux kinetics were very rapid such that accumulation by the cells was thermodynamically, not kinetically, controlled. Accumulation by human PBMCs in vitro was directly proportional to the free and not the total drug concentration in the media. For comparative purposes, the serum protein binding effect on the distribution of two HIV reverse transcriptase (RT) inhibitors, delavirdine (RESCRIPTOR) and zidovudine (AZT), was also evaluated. Like the HIV-1 protease inhibitors, delavirdine was found to be extensively associated with serum proteins and its accumulation by human PBMCs in vitro to be proportional to the free and not total drug concentration. In contrast, AZT was not bound to serum proteins to any significant extent. The uptake of this drug by human PBMCs in vitro was independent of serum concentration. However, the intrinsic cellular accumulation of PNU-96988, PNU-103017 and delavirdine were all greater than AZT. Thus, the extent to which drugs uptake by cells is affected by serum appears proportional to the binding affinity of the serum proteins for the drug.
authors.affiliation: Drug Metabolism Research, Pharmacia & Upjohn Inc, Kalamzoo, MI 49001, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Koeplinger
authors.forename: T J
authors.initials: TJ
authors.lastname: Raub
authors.forename: G E
authors.initials: GE
authors.lastname: Padbury
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D001798:Blood Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D015925:Cryopreservation; D020008:Delavirdine / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011485:Protein Binding; D011753:Pyrones / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D015215:Zidovudine / Q000493:pharmacokinetics
chemical_list: D001798:Blood Proteins; D017320:HIV Protease Inhibitors; C405223:PNU 96988; D011753:Pyrones; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; C107418:PNU 103017; D015215:Zidovudine; D020008:Delavirdine