罗景慧,杨迎暴
LUO Jing-hui1, YANG Ying-bao2 (1. Department of Pharmacy

• 1:南方医院药学部
• 2:南方医科大学药学院药理学系

摘要(Abstract)：

目的研究肾功能不全的情况下,血管紧张素转化酶抑制药依那普利的活性代谢产物依那普利拉在大鼠体内的药动学变化,探讨依那普利临床合理用药方法。方法16只大鼠随机分为两组,一组为正常对照组,另一组以阿霉素制备肾功能不全,分别灌胃给予依那普利(20mg/kg),按规定时间点取血并测定血浆中依那普利拉的血浆浓度,采用3P97拟合药动学模型并计算药动学参数。结果正常对照组与肾损伤模型组在单次给予依那普利后,依那普利拉Cmax分别为68.61±7.58、113.94±12.29ng/ml,tpeak分别为3.35±0.82、11.11±2.87h,t1/2分别为10.74±2.32、55.72±7.65h,AUC0-∞分别为1.36±0.18、10.72±2.05μg·ml-1·h-1,表明肾损伤可使依那普利位Cmax明显升高,tpeak和t1/2明显延长,AUC显著增大,两组间存在显著统计学差异。结论肾功能不全可使依那普利作用时间延长,体内药物蓄积,因此,在临床上用于肾功能不全患者特别是应用于糖尿病性肾病时,应注意正确调整给药方案。
Objective To investigate the effect of renal impairment on pharmacokinetics of enlaprilat, active metabolite of enalapril, angiotensin converting enzyme inhibitor, in rats. Methods A total of 16 rats were randomly divided into normal control group and renal impairment group induced by adriamycin, and then the rats were administrated with enalapril 20 mg/kg p.o. The plasma samples were gained, and the plasama concentration of enalaprilat, main metabolite of enalapril, was determined by HPLC-UV. Results After p.o. single dose enalapril 20 mg/kg, (Cmax)s of enalaprilat were 68.61 ±7.58 ng/ml for control group and 113.94 ±12.29 ng/ml for renal impairment group. Meantime, (tpeak)s were 3.35±0.82 h and 11.11±2.87 h,(t1/2)s were 10.74±2.32 h and 55.72±7.65 h,(AUC0-∞)s were 1.36±0.18 μg·ml-1·h-1 and 10.72±2.05 μg·ml-1·h-1, respectively, which showed statistical significance between 2 groups. Conclusion Renal impairment could prolong t1/2 significantly and augment the accumulation of enalapril. Therefore, it is important to correctly regulate the therapeutic scheme for using enalapril to treat renal impairment patients, especially, diabetic nephropathy.

关键词(KeyWords)： 依那普利;依那普利拉;肾损伤;药动学
enalapril; enalapilat; renal impairment; pharmacokinetics

Abstract:

Keywords:

基金项目(Foundation): 广东省医院药学研究基金资助(编号:2008A015)

作者(Author): 罗景慧,杨迎暴
LUO Jing-hui1, YANG Ying-bao2 (1. Department of Pharmacy

参考文献(References)：

• [1]Flint L.The role of ACE inhibitor therapy in treating cardiovascular disease[J].Nurs Times,2004,100(12):34-37.
• [2]Hamming I,Goor H,Navis GJ.ACE inhibitor use and the increased long-term risk of renal failure in diabetes[J].Kidney Int,2006,70(7):1377-1378.
• [3]Doulton TW,Saggar-Malik AK,He FJ,et al.The effect of sodium and angiotensin converting enzyme inhibition on the classic circulating renin angiotensisn system in autoso-mal-dominant polycystic kidney di-sease patients[J].J Hypertens,2006,24(5):939-945.
• [4]Lupi R,Del Guerra S,Bugliani M,et al.The direct effects of the angiotensin converting enzyme inh-ibitors,zofenoprilat and enalaprilat,on isolated human pancreatic islets[J].Eur J Endocrinol,2006,154(2):355-361.
• [5]Rugale C,Cordaillat M,Mimran A,et al.Prevention and reversal by enalapril of target organ damage in angiotensinⅡhypertension[J].J renin Angiotensin Aldosterone Syst,2005;6(3):154-160.
• [6]Bhushan R,Gupta D,Singh SK.Liquid chromatographic separation and UV determination of certain antihyertensive agent[J].Biomed Chromatogr,2006,20(2):217-224.
• [7]倪立,陆宏国,周春红,等.马来酸依那普利片相对生物利用度研究[J].江苏临床医学杂志,2002,6(3):230.
• [8]王淑君,姜晓薇,孙进,等.HPLC法测定依那普利的血药浓度[J].沈阳药科大学学报,2003,20(5):349-351.
• [9]Badris GL,Weir MR.Comparison of dual RAAS blockade and higher-dose RAAS inhibitionon nephropa-thy progression[J].Postgrad Med,2008,120(1):33-42.
• [10]Song JH,Cha SH,Hong SB,et al.Dual blockade of renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensinⅡreceptor blockers in chronic kidney disease[J].J Hypertens Suppl,2006,24(1):S101-106.