Drug Delivery Vehicle—Teriflunomide Interactions Affect Treatment and Fluorine Magnetic Resonance in an Animal Model of Multiple Sclerosis

Background/Objectives: Teriflunomide (TF) is a fluorinated oral therapy approved for relapsing-remitting multiple sclerosis that can be detected using fluorine-19 (19F) magnetic resonance (MR) methods. In preclinical studies, palatable drug delivery vehicles may facilitate voluntary oral administration and reduce procedure-related stress; however, they may also interact with the drug and alter its pharmacological and MR properties. We investigated whether sweetened milk (SM), compared with sucrose-containing carboxymethylcellulose (SCMC), affects the therapeutic efficacy, tissue distribution, and 19F MR signal of TF in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Methods: Twenty-four female SJL/J mice received TF (30 mg/kg/day) in SM or SCMC, or the corresponding vehicle controls, by micropipette-guided drug administration (MDA) from day −2 to day 22. Clinical disease was monitored; hepatic TF was assessed ex vivo by 19F MR spectroscopy (MRS) and imaging (MRI) at 9.4 T; and brain TF was quantified by HPLC-MS. Formulation-dependent 19F MR spectral and MR relaxation properties were examined in vitro using phantoms containing TF in different vehicles, including DMSO, SM, SCMC, and serum. Intrinsic pharmacodynamic activity was evaluated by dihydroorotate dehydrogenase (DHODH) inhibition. Results: TF in SCMC reduced EAE severity during peak disease and delayed disease onset, whereas TF in SM produced no sustained therapeutic benefit. Hepatic 19F MR signals were approximately twofold higher with SCMC than with SM, and brain TF concentrations were 4.8-fold higher. Phantom studies revealed formulation-dependent changes in chemical shift, spectral linewidth, and the MRI relaxation time T2, including a 65-fold shortening in CMC + SM relative to CMC alone. SM did not reduce the intrinsic DHODH inhibitory potency of TF, indicating that the diminished in vivo efficacy was not attributable to impaired pharmacodynamic activity. Conclusions: As an oral delivery vehicle, sweetened milk altered TF therapeutic efficacy, as well as 19F MR signal and tissue distribution in the EAE model. Palatable vehicles used for voluntary oral treatment should therefore be carefully selected and validated, as vehicle–drug interactions may alter tissue exposure, confound 19F MR detection and, more importantly, compromise therapeutic efficacy.