皮下埋植缬沙坦缓释制剂对自发性高血压大鼠血压及血药浓度的影响

［摘要］目的: 探讨皮下埋植缬沙坦缓释制剂对自发性高血压大鼠（spontaneously hypertensive rat， SHR）血压及血药浓度的影响。方法: 将缬沙坦原药装入药用硅胶管并密封制作成可皮下埋植的缓释制剂；将SHR随机分为空白对照组、埋植组、灌胃组，每组5只。空白组、埋植组大鼠分别于皮下植入空白硅胶管、缬沙坦缓释制剂（100 mg/s），灌胃组用缬沙坦每天灌胃（16 mg/kg），另以5只Wistar大鼠作为正常对照组行假手术。各组均干预15 d。定期测量大鼠尾动脉血压，并采集静脉血，采用超高相液相色谱串联质谱法检测缬沙坦血药浓度。结果： 干预7 d后，埋植组、灌胃组SHR收缩压均明显低于空白组SHR（P<0.05），与正常对照组SHR无统计学差别（P>0.05），埋植组与灌胃组SHR收缩压间差异无统计学意义（P>0.05）；这种趋势一直维持至干预结束。用药2 h后，埋植组SHR缬沙坦血药浓度达到稳定水平，灌胃组SHR血药浓度在服药2 h达峰值，为埋植组SHR血药浓度的4.8倍；此后，灌胃组血药浓度逐渐下降，于第24小时低于埋植组；48 h后至干预结束，灌胃组SHR血药浓度与埋植组SHR无统计学差别。结论： 与口服途径相比，皮下埋植缬沙坦缓释制剂，仅用药1次，即可达到与每天口服药物一样的目标血压长达2周，并能维持更为稳定的血药浓度。

Effects of subcutaneously implanted sustained-release valsartanpreparation on systolic pressure and its plasma concentration in spontaneously hypertensive rats

Abstract\]Objective: To examine the  effectiveness of subcutaneously implanted sustained release valsartan preparation on systolic pressure and plasma drug concentration in spontaneously hypertensive rat(SHR). Methods: The valsartan original medicine was loaded into a silicone tube and sealed to be a sustained release preparation for subcutaneous implantation. SHR were randomly divided into blank control group(group A), valsartan implant group(group B), valsartan gavage group(group C), and SHR in group A and group B were implanted subcutaneously with blank silicone tube and sustained-release valsartan preparation(100 mg/s) respectively, and SHR in group C were administered with valsartan solutions［16 mg/(kg·d）］ by gavage. Healthy Wistar rats were used as the normal control group (group D), and the sham operation was performed. All groups were administered for fifteen days. Mean blood pressure of the rat tail artery and plasma concentration were monitored regularly. Results: Systolic pressure of SHR in group B and group C were lower than that of SHR in group A(P<0.05) after seven days of intervention, but there was no statistical difference found between group C and group B. This trend has been maintained until the end of the experiment. After two hours of treatment, the plasma level of valsartan of SHR in group B reached a stable level. However, the plasma level of valsartan of SHR reached the peak at 2 hours after first gavaged with valsartan in goup C, which was 4.8 times as high as that of SHR in group B. Then, plasma level of valsartan of SHR in group C decreased gradually, and was lower than that of SHR in group B(P<0.05) at twenty fourth hours(the next day, before gaving medicine). With gavaging by valsartan once a day, the lowest plasma level of valsartan of SHR in group C was increased gradually, and reached the level that of SHR in group B(P>0.05) after intervention of 48 hours, and remained this trend at the end of the experiment. Conclusion: Subcutaneous implantation of valsartan sustained-release preparation, only single treatment, can reduce SHR systolic pressure long and smoothly, and achieve a stable target blood pressure as well as oral drugs once day for 2 weeks, and maintain more stable plasma concentration. ［Key words］long acting antihypertention; subcutaneous implantation; sustained release antihypertensive agents; spontaneously hypertensive rat; plasma drug concentration