改进的替诺福韦酯前药的药代动力学增强了临床前模型中HBV

StephenW

改进的替诺福韦酯前药的药代动力学增强了临床前模型中HBV复制的抑制和肝细胞代谢的再平衡
洪晓丹 1 , 蔡祖焕 1 , 方舟 1 , 金晓亮 1 , 王广济 1 , 欧阳炳臣 2 , 张经纬 1
隶属关系
隶属关系

    1
    中国药科大学天然药物国家重点实验室药物代谢与药代动力学重点实验室，江苏南京。
    2
    【作者单位】： 江苏省南京市南京中医药大学附属医院;

    PMID：36105197 PMCID：PMC9465247 DOI：10.3389/fphar.2022.932934

抽象的

替诺福韦（TFV）酯前药是一类核苷酸类似物（NAs），是临床一线抗乙型肝炎病毒（HBV）药物，具有抗病毒作用强、耐药率低、安全性高等特点。在这项工作中，三种已上市的 TFV 酯类药物，即富马酸替诺福韦酯 (TDF)、艾拉酚胺富马酸替诺福韦酯 (TAF) 和阿米布芬富马酸替诺福韦酯 (TMF)，被用作探针，以研究前药结构、药代动力学特征、代谢激活、药理作用之间的关系。反应并揭示TFV酯前药设计的关键因素。结果表明，TMF 和 TAF 在 HBV 阳性 HepG2.2.15 细胞中对 HBV DNA 复制的抑制作用明显强于 TDF。治疗 9 天后，TMF 的抗 HBV 活性略强于 TAF（EC50 7.29 ± 0.71 nM 对 12.17 ± 0.56 nM）。在 HBV 转基因小鼠模型给药后的 HBV 衰退期也观察到了类似的结果，尽管这三种 TFV 前药在治疗 42 天后最终达到了相同的抗 HBV 效果。此外，TFV酯类前药对紊乱的宿主肝脏生化代谢，包括TCA循环、糖酵解、磷酸戊糖途径、嘌呤/嘧啶代谢、氨基酸代谢、酮体代谢和磷脂代谢有纠正作用。三种TFV酯类前药的回调作用排序为TMF>TAF>TDF。 TMF 的这些优势被认为归因于其在临床前动物（SD 大鼠、C57BL/6 小鼠和比格犬）中的更高生物利用度和更好的靶负荷，特别是在药理活性代谢物 TFV-DP 的更高肝脏水平方面，这与抗HBV疗效密切相关。进一步分析表明，肠液中的稳定性决定了TFV前药在吸收部位的实际含量，肝/肠稳定性决定了前药在循环中的维持量，两者均影响TFV前药的口服生物利用度。总之，我们的研究表明，改善 TFV 酯类前药的药代动力学（尤其是肠道稳定性）增强了对 HBV 复制的抑制和肝细胞代谢的再平衡，这为新的 TFV 前药的设计、修改和评估提供了新的见解和基础。未来。

关键词：抗HBV活性；酯类前药；脂质组学；代谢组学；药代动力学；替诺福韦。

版权所有 © 2022 Hong, Cai, Zhou, Jin, Wang, Ouyang and Zhang。
利益冲突声明

作者声明，该研究是在没有任何可能被解释为潜在利益冲突的商业或财务关系的情况下进行的。

StephenW

Improved pharmacokinetics of tenofovir ester prodrugs strengthened the inhibition of HBV replication and the rebalance of hepatocellular metabolism in preclinical models
Xiaodan Hong  1 , Zuhuan Cai  1 , Fang Zhou  1 , Xiaoliang Jin  1 , Guangji Wang  1 , Bingchen Ouyang  2 , Jingwei Zhang  1
Affiliations
Affiliations

    1
    Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
    2
    Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.

    PMID: 36105197 PMCID: PMC9465247 DOI: 10.3389/fphar.2022.932934

Abstract

Tenofovir (TFV) ester prodrugs, a class of nucleotide analogs (NAs), are the first-line clinical anti-hepatitis B virus (HBV) drugs with potent antiviral efficacy, low resistance rate and high safety. In this work, three marketed TFV ester drugs, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF) and tenofovir amibufenamide fumarate (TMF), were used as probes to investigate the relationships among prodrug structures, pharmacokinetic characteristics, metabolic activations, pharmacological responses and to reveal the key factors of TFV ester prodrug design. The results indicated that TMF and TAF exhibited significantly stronger inhibition of HBV DNA replication than did TDF in HBV-positive HepG2.2.15 cells. The anti-HBV activity of TMF was slightly stronger than TAF after 9 days of treatment (EC50 7.29 ± 0.71 nM vs. 12.17 ± 0.56 nM). Similar results were observed in the HBV decline period post drug administration to the HBV transgenic mouse model, although these three TFV prodrugs finally achieved the same anti-HBV effect after 42 days treatments. Furthermore, TFV ester prodrugs showed a correcting effect on disordered host hepatic biochemical metabolism, including TCA cycle, glycolysis, pentose phosphate pathway, purine/pyrimidine metabolism, amino acid metabolism, ketone body metabolism and phospholipid metabolism. The callback effects of the three TFV ester prodrugs were ranked as TMF > TAF > TDF. These advantages of TMF were believed to be attributed to its greater bioavailability in preclinical animals (SD rats, C57BL/6 mice and beagle dogs) and better target loading, especially in terms of the higher hepatic level of the pharmacologically active metabolite TFV-DP, which was tightly related to anti-HBV efficacy. Further analysis indicated that stability in intestinal fluid determined the actual amount of TFV prodrug at the absorption site, and hepatic/intestinal stability determined the maintenance amount of prodrug in circulation, both of which influenced the oral bioavailability of TFV prodrugs. In conclusion, our research revealed that improved pharmacokinetics of TFV ester prodrugs (especially intestinal stability) strengthened the inhibition of HBV replication and the rebalance of hepatocellular metabolism, which provides new insights and a basis for the design, modification and evaluation of new TFV prodrugs in the future.

Keywords: anti-HBV activity; ester prodrug; lipidomics; metabolomics; pharmacokinetics; tenofovir.

Copyright © 2022 Hong, Cai, Zhou, Jin, Wang, Ouyang and Zhang.
Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

StephenW

https://www.frontiersin.org/arti ... har.2022.932934/pdf