title: p16INK4a, a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV-Infected Subjects.
abstract: The goal of this study was to explore the relationships between tenofovir (TFV) and emtricitabine (FTC) disposition and markers of biologic aging, such as the frailty phenotype and p16INK4agene expression. Chronologic age is often explored in population pharmacokinetic (PK) analyses, and can be uninformative in capturing the impact of aging on physiology, particularly in human immunodeficiency virus (HIV)-infected patients. Ninety-one HIV-infected participants provided samples to quantify plasma concentrations of TFV/FTC, as well as peripheral blood mononuclear cell (PBMC) samples for intracellular metabolite concentrations; 12 participants provided 11 samples, and 79 participants provided 4 samples, over a dosing interval. Nonlinear mixed effects modeling of TFV/FTC and their metabolites suggests a relationship between TFV/FTC metabolite clearance (CL) from PBMCs and the expression of p16INK4a, a marker of cellular senescence. This novel approach to quantifying the influence of aging on PKs provides rationale for further work investigating the relationships between senescence and nucleoside phosphorylation and transport.
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Dumond
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Collins
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Cottrell
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Trezza
authors.affiliation: School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Hma
authors.initials: H
authors.lastname: Prince
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sykes
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: C
authors.initials: C
authors.lastname: Torrice
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: N
authors.initials: N
authors.lastname: White
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: S
authors.initials: S
authors.lastname: Malone
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Patterson
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Sharpless
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: A
authors.initials: A
authors.lastname: Forrest
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D000068679:Emtricitabine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D000068698:Tenofovir / Q000008:administration & dosage* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000068698:Tenofovir; D000068679:Emtricitabine