ACS Omega
·
2026
·
IF 5.2
Le-hao Jin,Zhe-yan Zhang,Xiao-yu Xu,Zhong-xi Chen,Jing Chen,Yu-bin Lan,Liu-liu Pan,Xiao-dan Zhang
Anastrozole and abemaciclib are clinically recommended in combination for the treatment of advanced breast cancer. However, the potential drug–drug interaction between them remains poorly characterized, posing a potential risk for altered drug exposure and toxicity. This study aimed to systematically investigate the effect of anastrozole on the metabolism and pharmacokinetics of abemaciclib. Using a combined in vitro and in vivo approach, we characterized this interaction via UPLC-MS/MS analysis of abemaciclib and its major metabolites (M2 and M20). In vitro enzymatic assays demonstrated that anastrozole significantly inhibits the metabolism of abemaciclib. Consistent with these findings, in vivo studies in female Sprague–Dawley rats showed that 7-day pretreatment with anastrozole prior to abemaciclib administration substantially decreased abemaciclib clearance, resulting in markedly increased systemic exposure (AUC0–t, AUC0–∞, and Cmax). Given that abemaciclib is predominantly metabolized by CYP3A4, we further examined whether genetic polymorphisms in this enzyme influence the observed interaction. Our results revealed that CYP3A4 genetic polymorphisms significantly modulate the inhibitory potency of anastrozole. These findings indicate that anastrozole acts as a CYP3A4 inhibitor, altering abemaciclib disposition in a genotype-dependent manner. This study highlights a clinically significant drug interaction with potential toxicological implications and provides a mechanistic basis for genotype-guided therapy in patients receiving this combination regimen.
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BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Tiantian Fu,Bingyi Yao,Yuanqing Guo,Yujia Yang,Junze Huang,Chenmeizi Liang,Yuanjin Zhang,Xin Wang
Patients with eclampsia are treated with antihypertensive drugs such as nifedipine and sedatives like chlorpromazine. The placenta, a unique organ connecting mother and baby, can regulate the intake and export of substances and mediate their metabolism. This report examined the metabolism of nifedipine in human placenta microsomes, with K m and V max values of 12.90 ± 1.01 μM and 39.33 ± 0.88 pmol/mg protein/min, respectively. Further research demonstrated that cytochrome P450 19A1 (CYP19A1) was the primary enzyme responsible for metabolizing nifedipine in the placenta, confirmed through selective inhibition, Jarrett (JAR) cell verification, recombinant enzyme identification, and metabolism correlation analysis using the CYP19A1-specific substrate androstenedione. Additionally, this study investigated the effect of chlorpromazine on nifedipine metabolism in the placenta. The results indicated that chlorpromazine competitively inhibited CYP19A1 activity in human placenta microsomes and CYP19A1 supersomes, thus decreasing nifedipine metabolism mediated by this enzyme. In brief, this study confirms that nifedipine is metabolized in the human placenta and can interact with chlorpromazine via CYP19A1-mediated pathways in in vitro conditions.
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高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-23
·
IF 14.7
Luo Yu-Wei,Zhou Jiang-Peng,Ji Hongyu,Xu Doudou,Zheng Anqi,Wang Xin,Dai Zhizheng,Luo Zhicheng,Cao Fang,Wang Xing-Yue,Bai Yunfang,Chen Di,Chen Yueming,Wang Qi,Yang Yaying,Zhang Xinghai,Chiu Sandra,Peng Xiaozhong,Huang Ai-Long,Tang Kai-Fu
Though RNAi and RNA-splicing machineries are involved in regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, their precise roles in coronavirus disease 2019 (COVID-19) pathogenesis remain unclear. Herein, we show that decreased RNAi component (Dicer and XPO5) and splicing factor (SRSF3 and hnRNPA3) expression correlate with increased COVID-19 severity. SARS-CoV-2 N protein induces the autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, inhibiting miRNA biogenesis and RNA splicing and triggering DNA damage, proteotoxic stress, and pneumonia. Dicer, XPO5, SRSF3, and hnRNPA3 knockdown increases, while their overexpression decreases, N protein-induced pneumonia’s severity. Older mice show lower expression of Dicer, XPO5, SRSF3, and hnRNPA3 in their lung tissues and exhibit more severe N protein-induced pneumonia than younger mice. PJ34, a poly(ADP-ribose) polymerase inhibitor, or anastrozole, an aromatase inhibitor, ameliorates N protein- or SARS-CoV-2-induced pneumonia by restoring Dicer, XPO5, SRSF3, and hnRNPA3 expression. These findings will aid in developing improved treatments for SARS-CoV-2-associated pneumonia.
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