Ailabouni Anoud Sameer, Vijaywargi Gautam, Subash Sandhya, Singh Dilip Kumar, Gaborik Zsuzsanna, Prasad Bhagwat
Department of Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA.
Charles River Laboratories Hungary Kft, H-1117 Budapest, Hungary.
Metabolites. 2025 Jan 29;15(2):80. doi: 10.3390/metabo15020080.
The impact of potential precipitant drugs on plasma or urinary exposure of endogenous biomarkers is emerging as an alternative approach to evaluating drug-drug interaction (DDI) liability. 1-Methylnicotinamide (NMN) has been proposed as a potential biomarker for renal organic cation transporter 2 (OCT2). NMN is synthesized in the liver from nicotinamide by nicotinamide N-methyltransferase (NNMT) and is subsequently metabolized by aldehyde oxidase (AO). Multiple clinical studies have shown a reduction in NMN plasma concentration following the administration of OCT inhibitors such as cimetidine, trimethoprim, and pyrimethamine, which contrasts with their inhibition of NMN renal clearance by OCT2. We hypothesized that OCT1-mediated NMN release from hepatocytes is inhibited by the administration of OCT inhibitors. Re-analysis of the reported NMN pharmacokinetics with and without OCT inhibitor exposure was performed. We assessed the effect of cimetidine on NMN uptake in OCT1-HEK293 cells and evaluated the potential confounding effects of cimetidine on enzymes involved in NMN formation and metabolism. A re-analysis of previous NMN pharmacokinetic DDI data suggests that NMN plasma systemic exposure decreased by 17-41% during the first 4 h following different OCT inhibitor administration except dolutegravir. Our findings indicate that NMN uptake was significantly higher (by 2.5-fold) in OCT1-HEK293 cells compared to mock cells, suggesting that NMN is a substrate of OCT1. Additionally, our results revealed that cimetidine does not inhibit NNMT and AO activity. Our findings emphasize the limitations of using NMN as an OCT2 biomarker and reveal potential mechanisms behind the reduction in NMN plasma levels associated with OCT inhibitors. Instead, our data suggest that NMN could be tested further as a potential biomarker for OCT1 activity.
潜在促发药物对内源性生物标志物血浆或尿液暴露的影响正成为评估药物相互作用（DDI）风险的一种替代方法。1-甲基烟酰胺（NMN）已被提议作为肾有机阳离子转运体2（OCT2）的潜在生物标志物。NMN由烟酰胺通过烟酰胺N-甲基转移酶（NNMT）在肝脏中合成，随后被醛氧化酶（AO）代谢。多项临床研究表明，服用西咪替丁、甲氧苄啶和乙胺嘧啶等OCT抑制剂后，NMN血浆浓度会降低，这与其通过OCT2抑制NMN肾清除率形成对比。我们假设，服用OCT抑制剂会抑制OCT1介导的NMN从肝细胞的释放。我们对已报道的有无OCT抑制剂暴露情况下的NMN药代动力学进行了重新分析。我们评估了西咪替丁对OCT1-HEK293细胞中NMN摄取的影响，并评估了西咪替丁对参与NMN形成和代谢的酶的潜在混杂效应。对先前NMN药代动力学DDI数据的重新分析表明，除多替拉韦外，在服用不同OCT抑制剂后的前4小时内，NMN血浆全身暴露量降低了17%-41%。我们的研究结果表明，与mock细胞相比，OCT1-HEK293细胞中NMN摄取显著更高（高2.5倍），表明NMN是OCT1的底物。此外，我们的结果显示西咪替丁不抑制NNMT和AO活性。我们的研究结果强调了将NMN用作OCT2生物标志物的局限性，并揭示了与OCT抑制剂相关的NMN血浆水平降低背后的潜在机制。相反，我们的数据表明，NMN作为OCT1活性的潜在生物标志物可进一步进行测试。
