Pharmacokinetics and tissue distribution of NXC736, a novel modulator for sphingosine-1 phosphate receptor 1 and 4, in rats

초록

Purpose NXC736, a novel compound that acts on sphingosine-1-phosphate (S1P) receptor 1 and 4, can treat autoimmune disease. We aimed to develop and validate the analytical method for NXC736 and its active metabolite NXC736-phosphate and to assess their pharmacokinetics and tissue distribution in rats. Methods We conducted animal studies to evaluate the oral absorption, distribution, excretion, and toxicokinetics of NXC736 and NXC736-phosphate in rats. Results NXC736 is converted to NXC736-phosphate via sphingosine kinase pre-systemically and in the body after absorption. NXC736 exhibited rapid absorption and high hepatic clearance and was eliminated with half-life of 3–5 h. Dose normalized plasma exposure of NXC736 showed dose dependency in an oral dose range of 3–30 mg/kg and became saturated in the dose range of 37.5–150 mg/kg. Subsequently, the NXC736-phosphate conversion rate was decreased dose-dependently, suggesting sphingosine kinase saturation. After the repeated oral administration of NXC736 (37.5–150 mg/kg) for 28 days, NXC736-phosphate accumulation was less than 2-fold, and no toxicity was observed in any rat. Blood lymphocyte inhibition, a pharmacological marker for NXC736, occurred by approximately 35%, 53%, and 56% at NXC736 doses of 37.5, 75, and 150 mg/kg/day, respectively, but recovered in a few days to control levels, suggesting NXC736 exhibits reversible activity. Conclusion These findings provided crucial insights into the pharmacokinetic profiles of NXC736 and NXC736-phosphate, including absorption, distribution, metabolism, and excretion, and can help bridge research into human studies and in planning and interpreting clinical trials.

키워드