摘要
目的研究地塞米松(Dex)高分子前药(P-Dex)对佐剂性关节炎(AIA)大鼠的疗效及其组织分布。方法于大鼠后足跖皮内注射完全弗氏佐剂建立关节炎大鼠模型,模型大鼠随机分为对照组、实验组和模型组,设健康大鼠空白组(均n=6)。对照组给予地塞米松磷酸钠(Dsp),试验组给予P-Dex,模型组与空白组给予生理盐水。建模前和建模后每3 d测定后肢踝关节直径和足掌厚度,给药后14 d取踝关节组织HE染色评价P-Dex对大鼠关节炎的治疗作用;超高效液相色谱-质谱串联法测定给药后不同时间点模型大鼠血浆、心、肝、脾、肺、肾及踝关节组织中Dex浓度,用DAS 2.0软件计算其药动学和组织分布参数。以踝关节对P-Dex和Dsp的相对摄取率及P-Dex对踝关节靶向效率为炎性关节靶向性评价指标对P-Dex靶向炎性关节特性进行评价。结果试验组给药后8 d踝关节直径及足掌厚度变化值明显小于对照组和模型组(P<0.05);试验组滑膜增生、软骨损坏较对照组和模型组轻,接近空白组。实验组PDex血浆t_(1/2)为32 h,血浆CL为(0.81±0.01)×10^(-4) L·h^(-1)·kg^(-1),AUC_(0-∞)为(3 135 973±1 932)ng·L^(-1)·h,是对照组Dsp的350倍。P-Dex主要分布在血浆、脾和肝中,游离Dex在踝关节组织中浓度最高。踝关节组织中P-Dex相对于Dsp的相对摄取率为1.22;Dsp和P-Dex靶向踝关节效率分别为9%和82%。结论 P-Dex具有较Dsp更为持久的抑制炎症作用,能够靶向于踝关节炎症部位,并在炎症部位选择性释放Dex。
AIM To evaluate the effects of dexamethasone （Dex） macromolecular prodrug （P- Dex） on adjuvant- induced arthritis （AIA） of rats and study the distribution of P- Dex in rat tissues. METHODS Complete Freund＇ s adjuvant was intradermally injected in hind limb to establish rat models of arthritis. Rats with AIA were randomly divided into control group （treated with dexamethasone sodium phosphate （Dsp））, test group （treated with P-Dex） and model group （treated with saline）, n = 6 in each group. A group of healthy rats （n = 6） were treated with saline as blank group. Therapeutical effect was evaluated by measuring the diameter of hind ankle and feet thickness every 3 days before and after the modeling. Pathological changes in ankle were observed by HE staining after 14 days of the treatment. The concentrations of Dex in plasma, heart, liver, spleen, lung, kidney and ankle were determined by ultra performance liquid chromatography- tandem mass spectrometric （UPLC- MS/MS） after different times of the treatment. Pharmacokinetics and distribution parameters were calculated by DAS 2.0. The targeting capability of P-Dex in inflammatory joints was studied by exploring the intake rate of P-Dex relative to that of Dsp and the targeting efficiency of P-Dex. RESULTS Both the variation of ankle diameter and the feet thickness in test group were less than those in the control group or model group （P 〈 0.05） after 8 days of the treatment. Synovial cell lining hyperplasia and cartilage damage were slighter than those in the control group and model group, and were close to those in the blank group, tin was 32 h, the plasma CL was （0.81±0.01） × 10-4 L.h-1.kg-1, AUC0-∞ was （3 135 973 ± 1 932） ng.L-1-h, which was 350 times higher than that of Dsp. P-Dex mainly distributed in plasma, liver and spleen, whereas free Dex mostly retained in ankle. The relative intake rate of P-Dex relative to that of Dsp in ankle was 1.22. The targeting efficiency of Dsp and free Dex was 9% and 82%, res
出处
《中国新药与临床杂志》
CAS
CSCD
北大核心
2016年第5期362-368,共7页
Chinese Journal of New Drugs and Clinical Remedies
基金
重庆市卫生局医学科研项目(2012-2-142)
重庆市卫生局医学科研项目(2012-2-22)
重庆市国际科技合作计划项目(cstc201110001)
关键词
地塞米松
前药
药效学
组织分布
靶向
dexamethasone
prodrug
pharmacodynamics
tissue distribution
target
