Leukotriene Receptor Antagonists Inhibit SLC19A1 and SLC46A1-Mediated Transport of Folic Acid and Antifolates.

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.