Effect of alcohol exposure on the efficacy and safety of tenofovir alafenamide fumarate, a major medicine against human immunodeficiency virus.
Effect of alcohol exposure on the efficacy and safety of tenofovir alafenamide fumarate, a major medicine against human immunodeficiency virus.
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DOI：
10.1016/j.bcp.2022.115224
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发表时间：
2022-10
影响因子：
5.8
通讯作者：
Yan, Bingfang
中科院分区：
文献类型：
--
作者：
Liu, William;Yu, Sarah;Yan, Bingfang
关键词：
人体免疫机能丧失病毒（艾滋病毒）仍然是一个重大的健康问题。与艾滋病有关的死亡（获得性免疫缺陷综合征）最近有所减少，但慢性肝病现在是艾滋病毒患者死亡的主要原因。普遍使用酒精被认为是一个主要因素。富马酸替诺福韦艾拉酚胺（TAF）是最常用的HIV药物之一，需要水解，然后磷酸化以产生最终抗HIV代谢物二磷酸替诺福韦。羧酸酯酶-1（CES 1），建立水解TAF，已知催化酯交换反应在乙醇的存在下。本研究的目的是检验TAF和乙醇之间基于代谢的相互作用对TAF的疗效和安全性产生负面影响的假设。为了检验这一假设，在存在或不存在乙醇的情况下，在人原代肝细胞和大量人肝脏样品（S9组分）中测定了TAF的代谢。通过LC-MS/MS（液相色谱串联质谱法）监测代谢，并通过Western印迹法测定CES 1或CES 2水平。与该假设一致，TAF在乙醇存在下发生酯交换反应，同时水解减少。替诺福韦二磷酸盐（治疗活性代谢物）的形成显著减少。此外，TAF，而不是其水解代谢产物，被发现增加细胞内的脂质潴留，并增加乙醇。这些研究结果得出结论，酒精消费，除了普遍接受的艾滋病毒药物依从性差，直接影响TAF的疗效和安全性。
Human immunodeficiency virus (HIV) continues to be a major health concern. AIDS-related deaths (acquired immunodeficiency syndrome) have decreased recently, but chronic liver disease is now a major cause of mortality among HIV patients. Widespread alcohol use is recognized to be a major contributing factor. Tenofovir alafenamide fumarate (TAF), one of the most used HIV drugs, requires hydrolysis followed by phosphorylation to produce tenofovir diphosphate, the ultimate anti-HIV metabolite. Carboxylesterase-1 (CES1), established to hydrolyze TAF, is known to catalyze transesterification in the presence of ethanol. The aim of the study was to test the hypothesis that metabolism-based interactions between TAF and ethanol negatively impact both efficacy and safety of TAF. To test this hypothesis, the metabolism of TAF was determined in human primary hepatocytes and with a large number of human liver samples (S9 fractions) in the presence or absence of ethanol. The metabolism was monitored by LC-MS/MS (liquid chromatography with tandem mass spectrometry) and the level of CES1 or CES2 was determined by Western blotting. Consistent with the hypothesis, TAF underwent transesterification in the presence of ethanol accompanied by decreased hydrolysis. The formation of tenofovir diphosphate (the therapeutically active metabolite) was significantly decreased. In addition, TAF but not its hydrolytic metabolite, was found to increase intracellular lipid retention, and the increase was enhanced by ethanol. These findings conclude that alcohol consumption, beyond commonly accepted poor adherence to HIV medications, directly impacts the efficacy and safety of TAF.
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影响因子：
--
作者：
Chowta MN;Kamath P;Ramapuram JT;Shenoy KA;Hadigal S
通讯作者：
Hadigal S
DOI：
10.1177/23259582211044920
发表时间：
2021-01
影响因子：
--
作者：
Brown JL;Anastasakis I;Revzina N;Capasso A;Boeva E;Rassokhin V;Crusey A;Sales JM;Hitch A;Renfro T;DiClemente RJ
通讯作者：
DiClemente RJ
影响因子：
3.9
作者：
Jaiswal J;Dunlap K;Griffin M;Cox A;Singer SN;Hascher K;LoSchiavo C;Walters SM;Mumba M
通讯作者：
Mumba M
影响因子：
2.9
作者：
Bavinton BR;Mahendra IGAA;Kaldor J;Law M;Grulich AE;Januraga PP
通讯作者：
Januraga PP
影响因子：
3.3
作者：
Duko, Bereket;Toma, Alemayehu;Abraham, Yacob
通讯作者：
Abraham, Yacob