Evaluating the efficacy and safety of 2-methoxy-6-methylpyridine: a promising topical agent for gallstone dissolution in a porcine model

While methyl-tertiary butyl ether (MTBE) remains the sole clinical topical agent for gallstone dissolution, its utility is limited due to side effects, largely stemming from its relatively low boiling point (55°C). In this study, we introduced 2-methoxy-6-methylpyridine (MMP), a novel gallstone-dissolving compound featuring an aromatic moiety and a substantially higher boiling point (156°C), designed to mitigate these side effects. We conducted a comprehensive evaluation of the efficacy and potential toxicities of MMP compared to MTBE using both in vitro and in vivo models. In the in vitro setting, MMP demonstrated significantly higher solubility than MTBE, achieving dissolution rates of 75% vs. 56%, 95% vs. 69%, and 100% vs. 82% at 60, 120, and 240 minutes, respectively (P < 0.05). In a porcine model with cholesterol gallstones, solubility assessments via direct injection of each solvent into the gallbladder showed that MMP exhibited approximately 1.8 times higher solubility compared to MTBE (P < 0.05). Further pharmacokinetic analysis in SD rats revealed that MMP is rapidly absorbed and efficiently cleared from the bloodstream, with dose-dependent variations in half-life, indicating favorable excretion profiles. Toxicological assessments in both rodents and pigs showed that MMP induces significantly less tissue damage than MTBE, with lower levels of apoptosis and inflammation in vital organs, as confirmed by molecular analyses including real-time PCR, Western blotting, and immunohistochemistry. Our findings indicate that MMP offers superior efficacy in cholesterol gallstone dissolution and presents a significantly lower toxicological profile, suggesting its potential as a safer and more effective alternative to MTBE.