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衰老标志物p16影响HIV感染受试者中替诺福韦/恩曲他滨代谢物的处置。

p16 , a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV-Infected Subjects.

作者信息

Dumond J B, Collins J W, Cottrell M L, Trezza C R, Prince Hma, Sykes C, Torrice C, White N, Malone S, Wang R, Patterson K B, Sharpless N E, Forrest A

机构信息

UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

出版信息

CPT Pharmacometrics Syst Pharmacol. 2017 Feb;6(2):120-127. doi: 10.1002/psp4.12150. Epub 2016 Dec 26.

DOI:10.1002/psp4.12150
PMID:28019088
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5321809/
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 p16 gene 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 p16 , 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.

摘要

本研究的目的是探讨替诺福韦（TFV）和恩曲他滨（FTC）的处置与生物衰老标志物之间的关系，如衰弱表型和p16基因表达。在群体药代动力学（PK）分析中经常探讨实际年龄，但在捕捉衰老对生理学的影响方面可能并无信息价值，尤其是在人类免疫缺陷病毒（HIV）感染患者中。91名HIV感染参与者提供了样本，用于定量TFV/FTC的血浆浓度，以及外周血单个核细胞（PBMC）样本以测定细胞内代谢物浓度；在一个给药间隔内，12名参与者提供了11份样本，79名参与者提供了4份样本。TFV/FTC及其代谢物的非线性混合效应模型表明，PBMC中TFV/FTC代谢物清除率（CL）与细胞衰老标志物p16的表达之间存在关联。这种量化衰老对药代动力学影响的新方法为进一步研究衰老与核苷磷酸化及转运之间的关系提供了理论依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d000/5321809/d487b764f2f2/PSP4-6-120-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d000/5321809/cda06c1a2f4a/PSP4-6-120-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d000/5321809/cd466f0372fa/PSP4-6-120-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d000/5321809/d487b764f2f2/PSP4-6-120-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d000/5321809/cda06c1a2f4a/PSP4-6-120-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d000/5321809/cd466f0372fa/PSP4-6-120-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d000/5321809/d487b764f2f2/PSP4-6-120-g003.jpg

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