沙格列汀与穿心莲内酯在2型糖尿病大鼠体内的药动学相互作用及降糖作用

IF 0.4 4区 医学 Q4 PHARMACOLOGY & PHARMACY Acta poloniae pharmaceutica Pub Date : 2023-10-23 DOI:10.32383/appdr/170911
Suyan Wu, Haifei Pan, Yingying Huang
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引用次数: 0

摘要

控制血糖是2型糖尿病的主要治疗策略。沙格列汀和穿心莲内酯都有降糖作用,这使得联合使用很容易。本研究旨在评估沙格列汀和穿心莲内酯在大鼠中的联合应用,并揭示它们对2型糖尿病(T2DM)的联合影响。采用高脂饮食和注射烟酰胺、链脲佐菌素建立T2DM大鼠模型。造模后监测血糖和胰岛素抵抗指数。口服沙格列汀10 mg/kg,评价沙格列汀的药代动力学。同时给予30或100 mg/kg穿心莲内酯预处理。体外研究沙格列汀在大鼠肝微粒体中的代谢稳定性。沙格列汀与穿心莲内酯合用可引起沙格列汀药代动力学的显著变化,表现为AUC(0-t)、Cmax、t1/2升高,清除率降低。穿心莲内酯的作用随浓度的增加而增强。与穿心莲内酯联用可增强沙格列汀对T2DM大鼠的降糖作用,减轻沙格列汀的胰岛素抵抗。沙格列汀与100 mg/kg穿心莲内酯联合用药可引起低血糖。在体外实验中,穿心莲内酯显著提高了沙格列汀的代谢稳定性,对CYP3A4的活性有明显的抑制作用。沙格列汀与穿心莲内酯联用可通过抑制CYP3A4增加沙格列汀的全身暴露,改善降糖效果,但高浓度的穿心莲内酯存在诱发低血糖的风险。
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Pharmacokinetic interaction of saxagliptin with andrographolide and their hypoglycemic effect in type 2 diabetes rats
Controlling blood glucose is the primary therapeutic strategy for T2DM. Both saxagliptin and andrographolide possess hypoglycemic effects, which makes the combination easy. This study aimed to evaluate the co-administration of saxagliptin and andrographolide in rats and revealed their combined impact on type 2 diabetes (T2DM). T2DM rat models were established by high-fat diet and the injection of nicotinamide and streptozotocin. The blood glucose and insulin resistance index were monitored after modeling. The pharmacokinetics of saxagliptin was assessed by orally administrating 10 mg/kg saxagliptin. The co-administration was performed with the pre-treatment of 30 or 100 mg/kg andrographolide. In vitro, the metabolic stability of saxagliptin was assessed in rat liver microsomes. The co-administration of saxagliptin with andrographolide induced significant changes in the pharmacokinetics of saxagliptin, behaving as the increasing AUC(0-t), Cmax, t1/2, and the decreasing clearance rate. The effect of andrographolide was enhanced with the growing concentration. Combination with andrographolide enhanced the hypoglycemic effect and alleviated insulin resistance of saxagliptin in T2DM rats. Co-administration of saxagliptin with 100 mg/kg andrographolide induced hypoglycemia. In vitro, andrographolide significantly improved the metabolic stability of saxagliptin and showed a significant inhibitory effect on the activity of CYP3A4. Combining saxagliptin with andrographolide could increase the systemic exposure of saxagliptin via inhibiting CYP3A4 and improve the hypoglycemic effect, but the high concentration of andrographolide is the risk of inducing hypoglycemia.
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来源期刊
CiteScore
0.80
自引率
0.00%
发文量
74
审稿时长
6-12 weeks
期刊介绍: The international journal of the Polish Pharmaceutical Society is published in 6 issues a year. The journal offers Open Access publication of original research papers, short communications and reviews written in English, in all areas of pharmaceutical sciences. The following areas of pharmaceutical sciences are covered: Analysis, Biopharmacy, Drug Biochemistry, Drug Synthesis, Natural Drugs, Pharmaceutical Technology, Pharmacology and General. A bimonthly appearing in English since 1994, which continues “Acta Poloniae Pharmaceutica”, whose first issue appeared in December 1937. The war halted the activity of the journal’s creators. Issuance of “Acta Poloniae Pharmaceutica” was resumed in 1947. From 1947 the journal appeared irregularly, initially as a quarterly, then a bimonthly. In the years 1963 – 1973 alongside the Polish version appeared the English edition of the journal. Starting from 1974 only works in English are published in the journal. Since 1995 the journal has been appearing very regularly in two-month intervals (six books a year). The journal publishes original works from all fields of pharmacy, summaries of postdoctoral dissertations and laboratory notes.
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