Uterine first-pass effect: Unlocking the potential of vaginally administered ritodrine-loaded thermosensitive gel for uterine drug delivery

Preterm birth (PTB) remains a leading cause of infant mortality and morbidity, significantly affecting the long-term health, welfare, and development of newborns. Tocolytics, such as ritodrine, a β₂-adrenergic receptor agonist, are widely used in developing countries due to their affordability for preventing PTB by inhibiting uterine contractions. However, ritodrine's short half-life necessitates frequent administration, and prolonged high-dose usage often leads to serious maternal side effects, prompting discontinuation. The uterine first-pass effect, where vaginally administered drugs preferentially target the uterus, can enhance drug concentration in uterine tissue while minimizing systemic absorption and side effects. This study designed a kind of ritodrine-loaded thermosensitive gel (Gel@Rit) to intervene in PTB by exploiting the uterine first-pass effect and investigate its underlying mechanisms. The gel, formulated with poloxamer, demonstrated excellent temperature sensitivity and viscosity, ensuring sustained ritodrine release in vitro. Plasma pharmacokinetic and tissue distribution studies in pregnant mice confirmed the uterine first-pass effect, showing significantly higher drug concentrations in the uterus and markedly lower plasma levels following Gel@Rit administration. The distinctive drug-time curve in Gel@Rit-treated mice, along with uterine tissue fluorescence profiles, elucidated four mechanisms of uterine localization: diffusion through reproductive tract cavities, penetration via vaginal and uterine structures, diffusion through systemic circulation, and retrograde transvaginal veno-uterine artery exchange. This study provides valuable insights into vaginal drug delivery research methodologies, advancing therapeutic strategies for uterine-related conditions and benefiting clinical outcomes in PTB prevention.