白三烯受体拮抗剂抑制SLC19A1和SLC46A1介导的叶酸和抗叶酸药物转运
Leukotriene receptor antagonists inhibit SLC19A1 and SLC46A1-mediated transport of folic acid and antifolates.
文献信息
| PMID | 42716456 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Jun Luo |
| 作者单位 | Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China; Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. |
| 期刊 | Chemico-biological interactions |
| SCI 分区 | Q1 |
| IF | 5.5 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 鼻科 |
中文摘要
叶酸和抗叶酸药物依赖SLC19A1和SLC46A1进行膜转运，这对它们的生物学功能和治疗效果至关重要。白三烯受体拮抗剂（LTRAs）广泛用于哮喘和过敏性鼻炎的长期管理。本研究旨在探讨四种LTRAs（MK571、孟鲁司特、扎鲁司特、普仑司特）对SLC19A1和SLC46A1活性的影响。体外研究表明，MK571、孟鲁司特、扎鲁司特和普仑司特浓度依赖性地抑制SLC19A1和SLC46A1介导的叶酸、甲氨蝶呤和培美曲塞摄取，对SLC19A1的IC50值为2.34至31.8 μM，对SLC46A1的IC50值为2.79至45.4 μM。动力学分析揭示了不同的、转运体特异性的抑制机制：LTRAs作为SLC19A1的非竞争性抑制剂（Kᵢ = 5.09-6.71 μM），并作为SLC46A1的反竞争性抑制剂（Kᵢ = 4.12-95.1 μM）。小鼠体内药代动力学研究表明，联合给予孟鲁司特或扎鲁司特显著增加了叶酸的全身暴露量（AUC和Cmax）并延长了其半衰期，同时减少了其肝脏蓄积。综上所述，本研究将LTRAs鉴定为关键叶酸转运体SLC19A1和SLC46A1的新型强效抑制剂，并揭示了LTRAs与叶酸相关药物之间先前未被认识的转运体介导的药物相互作用。这些发现强调了在同时给药期间进行仔细临床监测和潜在剂量调整的必要性，以确保治疗安全性和有效性。
英文摘要
Folic acid and antifolates rely on SLC19A1 and SLC46A1 for membrane transport, which is critical for their biological functions and therapeutic efficacy. Leukotriene receptor antagonists (LTRAs) are widely used for long-term management of asthma and allergic rhinitis. This study aimed to explore the effects of four LTRAs (MK571, montelukast, zafirlukast, pranlukast) on the activities of SLC19A1 and SLC46A1. In vitro studies showed that MK571, montelukast, zafirlukast, and pranlukast concentration-dependently inhibited SLC19A1 and SLC46A1-mediated uptake of folic acid, methotrexate, and pemetrexed, with IC50 values ranging from 2.34 to 31.8 μM for SLC19A1 and 2.79 to 45.4 μM for SLC46A1. Kinetic analysis revealed distinct, transporter-specific inhibition mechanisms: LTRAs acted as noncompetitive inhibitors of SLC19A1 (Kᵢ = 5.09-6.71 μM) and as uncompetitive inhibitors of SLC46A1 (Kᵢ = 4.12-95.1 μM). In vivo pharmacokinetic studies in mice showed that co-administration of montelukast or zafirlukast significantly increased the systemic exposure (AUC and Cmax) and prolonged the half-life of folic acid, while reducing its hepatic accumulation. Taken together, this study identified LTRAs as novel and potent inhibitors of the key folate transporters SLC19A1 and SLC46A1, and uncovered previously unrecognized transporter-mediated drug-drug interactions between LTRAs and folate-related agents. These findings highlight the necessity of careful clinical monitoring and potential dose adjustments during concurrent administration to ensure therapeutic safety and efficacy.