Abstract：
The development of diabetes mellitus (DM) is generally accompanied by erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), which increases the use of combination drug therapy and the risk of drug-drug interactions. Saxagliptin for the treatment of DM, sildenafil for the treatment of ED and PAH, and macitentan for the treatment of PAH are all substrates of CYP3A4, which indicates their potential involvement in drug-drug interactions. Therefore, we investigated potential pharmacokinetic interactions between saxagliptin and sildenafil/macitentan. We investigated this speculation both in vitro and in vivo, and explored the underlying mechanism using in vitro hepatic metabolic models and molecular docking assays. The results showed that sildenafil substantially inhibited the metabolism of saxagliptin by occupying the catalytic site of CYP3A4 in a competitive manner, leading to the alterations in the pharmacokinetic properties of saxagliptin in terms of increased maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0-∞)), decreased clearance rate (CLz/F), and prolonged terminal half-life (t1/2). In contrast, a slight inhibition was observed in saxagliptin metabolism when concomitantly used with macitentan, as no pharmacokinetic parameters were altered, except for CLz/F. Thus, dosage adjustment of saxagliptin may be required in combination with sildenafil to achieve safe therapeutic plasma concentrations and reduce the risk of potential toxicity, but it is not necessary for co-administration with macitentan.
摘要：
糖尿病（DM）的发展通常伴有勃起功能障碍（ED）和肺动脉高压（PAH），这增加了联合药物治疗的使用和药物相互作用的风险。沙格列汀用于治疗DM，西地那非用于治疗ED和PAH，和用于治疗PAH的Macitentan都是CYP3A4的底物，这表明它们可能参与药物-药物相互作用。因此,我们调查了沙格列汀与西地那非/马西替坦之间潜在的药代动力学相互作用.我们在体外和体内研究了这种推测，并使用体外肝代谢模型和分子对接测定探索了潜在的机制。结果显示，西地那非通过竞争占据CYP3A4的催化位点，显著抑制沙格列汀的代谢，导致沙格列汀在最大血浆浓度（Cmax）增加方面的药代动力学特性发生改变，从时间0到24h的血浆浓度-时间曲线下面积（AUC（0-t）），从时间0外推至无限时间的血浆浓度-时间曲线下面积（AUC（0-∞）），清除率降低（CLz/F），和延长终末半衰期（t1/2）。相比之下,与马西坦一起使用时，沙格列汀代谢出现轻微抑制，因为药代动力学参数没有改变，除了CLz/F。因此，沙格列汀与西地那非合用时可能需要调整剂量，以达到安全的治疗血浆浓度并降低潜在毒性风险，但是没有必要与Macitentan共同管理。
