模拟热带海岛环境对炎性疼痛大鼠塞来昔布的药代动力学特征及疗效影响?

Effects of simulated tropical island environment on the pharmacokinetic profile and efficacy of celecoxib in rats with inflammatory pain

摘要:

目的 通过模拟热带海岛环境探究环境改变下炎性疼痛大鼠口服塞来昔布(Celecoxib,CXB)后药代动力学(pharmacokinetics, PK)特征和疗效的改变。 方法 2023年6月至2023年12月于上海长海医院选取雄性SD大鼠(体重200-250g)共66只,其中36只用于PK研究,30只用于痛阈研究。经随机数字表法共将大鼠分组后,分别于模拟热带海岛环境(温度34℃,湿度80%)和正常环境(温度20~25℃,湿度50~60%)中饲养3天适应环境。PK组大鼠经口服不同浓度CXB混悬液后采集血样通过高效液相色普法(High Performance Liquid Chromatography, HPLC)测定血清药物浓度；痛阈组予以左足弗氏完全佐剂注射以构建炎性疼痛模型,并予以口服不同浓度CXB混悬液后,Von Frey法测定大鼠机械刺激伤害感受阈、热板实验(hot plate test)测定热刺激伤害感受阈； 结果 本研究构建了稳定检测大鼠血清CXB浓度的HPLC体系；结果提示模拟热带海岛环境可改变大鼠口服CXB的PK特征,其中在中高剂量下,模拟热带海岛环境组大鼠的末端消除半衰期(t1/2)显著降低、AUC(0-t)及AUC(0-∞)均显著低于对照组、CL显著高于对照组；机械和热刺激伤害感受阈检测结果提示,模拟海岛环境组大鼠在注射后3天、4天、5天的多个时间节点的痛阈均显著低于对照组；模拟海岛环境可使大鼠肝脏中CXB代谢关键酶CYP2C9表达上升；模拟海岛环境可抑制CXB对炎性疼痛大鼠模型的抗炎作用,导致大鼠血清炎症因子升高。 结论 模拟热带海岛环境可改变大鼠口服CXB后的PK特征,导致药物代谢速度加快,并且降低药物抗炎镇痛效果。

Abstract:

Objective Alterations in pharmacokinetic profile and efficacy of Celecoxib (CXB) after oral administration to rats with inflammatory pain under environmental alterations explored by simulating a tropical island environment. Methods A total of 66 male SD rats (weighing 200-250 g) were selected from June 2023 to December 2023 at Changhai Hospital of the Naval Military Medical University, of which 36 were used for the pharmacokinetic (PK) study and 30 for the pain threshold study. The rats were grouped by randomized numerical table method and kept in simulated tropical island environment (34℃, 80% humidity) and normal environment (20-25℃, 50-60% humidity) for 3 days to acclimatize to the environment, and blood samples were collected from rats in the PK group after oral administration of different concentrations of CXB suspensions and were analyzed by High Performance Liquid Chromatography (HPLC). Blood samples were collected from rats in the PK group after oral administration of different concentrations of CXB suspension to determine serum drug concentration by High Performance Liquid Chromatography (HPLC); in the pain threshold group, rats in the PK group were injected with complete adjuvant from the left foot of the foot of the Fuchsia to construct a model of inflammatory pain, and then orally administered with different concentrations of CXB suspension to determine the threshold of sensation for mechanical stimulation injury by the Von Frey method, and the threshold of sensation for thermal stimulation injury by the hot plate test. Results An HPLC system was constructed for the stable detection of serum CXB concentration in rats; the results suggested that the simulated tropical island environment could change the PK characteristics of orally administered CXB in rats, in which the terminal elimination half-life (t1/2) of rats in the simulated tropical island environment group was significantly reduced at the middle and high doses, and the AUC (0-t) and AUC (0-∞) were significantly lower than those in the control group, and CL was significantly higher than that in the control group; The results of mechanical and thermal stimulation injury perception thresholds indicated that the pain thresholds of rats in the simulated island environment group were significantly lower than those of the control group at multiple time points, including 3, 4 and 5 days after injection; the simulated island environment increases the expression of CYP2C9, a key enzyme for CXB metabolism, in rat liver; the simulated island environment suppressed the anti-inflammatory effect of CXB on the rat model of inflammatory pain, resulting in the elevation of serum inflammation factor in the rats. Conclusion Simulated tropical island environment alters the pharmacokinetic profile of orally administered CXB in rats, leading to accelerated drug metabolism and reduced anti-inflammatory and analgesic effects of the drug.