绝经在宫颈组织中替诺福韦二磷酸和恩曲他滨三磷酸盐浓度中的作用。
The role of menopause in tenofovir diphosphate and emtricitabine triphosphate concentrations in cervical tissue.
机构信息
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota Twin Cities, Minneapolis, Minnesota.
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
出版信息
AIDS. 2018 Jan 2;32(1):11-15. doi: 10.1097/QAD.0000000000001678.
OBJECTIVE
Although postmenopausal (post-M) women have behavioral and biological risk factors for HIV infection, the activity of preexposure prophylaxis (PrEP) agents in older adults has not been well studied.
DESIGN
We used an ex-vivo approach to compare the tissue concentrations of tenofovir (TFV) diphosphate (TFVdp) and emtricitabine (FTC) triphosphate (FTCtp) in cervical tissues from premenopausal (pre-M) and post-M women.
METHOD
Cervical explants from 16 pre-M and 11 post-M women were incubated in 10-300 μg/ml TFV or FTC for 24 h. Explants were then snap frozen in liquid nitrogen and stored until analysis. TFVdp and FTCtp were quantified using tandem liquid chromatography-mass spectrometry.
RESULTS
Active metabolite concentrations of TFVdp were more than nine-fold lower in post-M explants (P < 0.05). The percentage of TFV converted to TFVdp in pre-M explants was 0.0038 [below the limit of quantification (BLQ)-0.5886] compared with 0.0004 (BLQ-0.0706) in post-M explants. The majority of FTCtp concentrations were BLQ. For both TFVdp and FTCtp, there was a trend for more unquantifiable concentrations in post-M vs. pre-M (TFV: 38 vs. 21%, P = 0.2; FTC: 71 vs. 52%, P = 0.2).
CONCLUSION
These findings could have implications in the use of nucleotide-based PrEP strategies targeted to older women. If validated in vivo, lower exposures of active nucleoside/tide metabolites could mean post-M women need higher doses of TFV-based PrEP to achieve protective efficacy.
目的
尽管绝经后（post-M）女性存在感染 HIV 的行为和生物学危险因素，但针对老年人群的暴露前预防（PrEP）药物的活性尚未得到充分研究。
设计
我们采用离体方法比较了来自绝经前（pre-M）和绝经后（post-M）女性宫颈组织中替诺福韦（TFV）二磷酸（TFVdp）和恩曲他滨（FTC）三磷酸（FTCtp）的组织浓度。
方法
将 16 名 pre-M 和 11 名 post-M 女性的宫颈标本在 10-300μg/ml TFV 或 FTC 中孵育 24 小时。然后将标本立即在液氮中冷冻并储存直至分析。使用串联液质联用技术定量测定 TFVdp 和 FTCtp。
结果
post-M 标本中 TFVdp 的活性代谢物浓度高出 9 倍（P<0.05）。与 pre-M 标本中的 0.0038（低于定量下限（BLQ）-0.5886）相比，post-M 标本中 TFV 转化为 TFVdp 的比例为 0.0004（BLQ-0.0706）。大多数 FTCtp 浓度低于定量下限。对于 TFVdp 和 FTCtp，post-M 标本中未定量浓度的趋势更为明显（TFV：38%比 21%，P=0.2；FTC：71%比 52%，P=0.2）。
结论
这些发现可能对针对老年女性的基于核苷酸的 PrEP 策略的使用产生影响。如果在体内得到验证，活性核苷/核苷酸代谢物的暴露量较低可能意味着 post-M 女性需要更高剂量的 TFV 基 PrEP 才能达到保护效果。
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