Xiao Ying, Hu Xuefeng, Xing Wei, Yan Jie, Wang Ruhuan, Li Xiaoqing, Li Jiahuan, Zhang Zhixin, Sun Jingchao, Wu Junjun
The Guangdong Provincial Key Laboratory of Cardiovascular Drug R and D Enterprises, Shenzhen Salubris Pharmaceuticals Co., Ltd., Shenzhen, Guangdong Province, China.
Front Pharmacol. 2024 Sep 24;15:1464564. doi: 10.3389/fphar.2024.1464564. eCollection 2024.
Esketamine, the first Food and Drug Administration-approved fast-acting antidepressant, has limited use because of its addictive properties. Although the combination of dextromethorphan and bupropion partially addresses the limitations of esketamine, concerns remain regarding neurologic side effects related to dextromethorphan metabolites, and seizure risks associated with high-dose bupropion. SAL0114, a novel formulation combining deuterated dextromethorphan (in which hydrogen atoms are replaced with deuterium) with bupropion, seeks to enhance dextromethorphan stability through deuteration of its metabolic sites. This approach is expected to increase antidepressant efficacy, reduce metabolite-induced safety issues, and allow for lower bupropion dosages.
Radioligand competition binding assays were used to evaluate the impact of deuterium substitution on the activity of dextromethorphan and its metabolite, dextrorphan. hepatic microsomal stability and mouse pharmacokinetic assays were performed to assess the effects of deuteration on dextromethorphan stability. Two mouse models of behavioral despair were used to determine the antidepressant and synergistic effects of deuterated dextromethorphan and bupropion. Additionally, a reserpine-induced hypothermia rat model and an ammonia-induced cough mouse model were used to assess the effects from a pathological perspective.
Deuterated dextromethorphan maintained the same activity as dextromethorphan while exhibiting twice the metabolic stability both and . Combination with bupropion further improved its stability, increasing the exposure by 2.4 times. The combination demonstrated efficacy and synergistic effects in all tested animal models, showing superior efficacy compared with the dextromethorphan-bupropion combination.
Deuteration improved dextromethorphan metabolic stability without altering its activity. Bupropion enhanced this stability and synergistically boosted the antidepressant effect by increasing deuterated dextromethorphan exposure . This enhanced metabolic stability suggests a reduction in dextromethorphan metabolites associated with clinical neurological side effects. Consequently, SAL0114 is hypothesized to offer improved efficacy and safety compared with the non-deuterated combination, potentially allowing for lower bupropion dosages. Further clinical studies are required to confirm these preclinical findings.
艾司氯胺酮是美国食品药品监督管理局批准的首个速效抗抑郁药，但因其成瘾性，其应用有限。尽管右美沙芬和安非他酮的组合部分解决了艾司氯胺酮的局限性，但与右美沙芬代谢物相关的神经副作用以及高剂量安非他酮相关的癫痫风险仍令人担忧。SAL0114是一种将氘代右美沙芬（氢原子被氘取代）与安非他酮结合的新型制剂，旨在通过对其代谢位点进行氘代来提高右美沙芬的稳定性。这种方法有望提高抗抑郁疗效，减少代谢物引起的安全问题，并允许使用更低剂量的安非他酮。
采用放射性配体竞争结合试验评估氘取代对右美沙芬及其代谢物右啡烷活性的影响。进行肝微粒体稳定性和小鼠药代动力学试验，以评估氘代对右美沙芬稳定性的影响。使用两种行为绝望小鼠模型来确定氘代右美沙芬和安非他酮的抗抑郁和协同作用。此外，使用利血平诱导的体温过低大鼠模型和氨诱导的咳嗽小鼠模型从病理学角度评估其效果。
氘代右美沙芬保持了与右美沙芬相同的活性，同时在体内和体外均表现出两倍的代谢稳定性。与安非他酮联合使用进一步提高了其稳定性，使暴露量增加了2.4倍。该组合在所有测试的动物模型中均显示出疗效和协同作用，与右美沙芬 - 安非他酮组合相比显示出更高的疗效。
氘代提高了右美沙芬的代谢稳定性，而不改变其活性。安非他酮增强了这种稳定性，并通过增加氘代右美沙芬的暴露量协同增强了抗抑郁作用。这种增强的代谢稳定性表明与临床神经副作用相关的右美沙芬代谢物减少。因此，假设SAL0114与未氘代的组合相比具有更高的疗效和安全性，可能允许使用更低剂量的安非他酮。需要进一步的临床研究来证实这些临床前研究结果。
