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| 注射用盐酸头孢他美对大鼠肝微粒体CYP1A2、CYP3A4和CYP2E1活性的影响 |
| 礼嵩1,2,3,唐原君1,何菁宇4,叶晓岚5,杨鹏4,李伟3*,范国荣1* |
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(1. 第二军医大学药学院药物分析学教研室,上海市药物(中药)代谢产物研究重点实验室,上海 200433
2. 第二军医大学长海医院泌尿外科GCP平台,上海 200433
3. 沈阳药科大学药学院药物分析学教研室,沈阳 110016
4. 福建中医药大学药学院,福州 350122
5. 广东药学院药物分析学教研室,广州 510000
*通信作者) |
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| 摘要: |
| 目的 研究注射用盐酸头孢他美对大鼠肝微粒体细胞色素P450(CYP450)酶系CYP1A2、CYP3A4和CYP2E1活性的影响。方法 将SD大鼠分成盐酸头孢他美给药组和生理盐水空白组,每组6只,雌雄各半,给药组尾静脉注射盐酸头孢他美50 mg/(kg·d),连续给药7 d,每天2次。HPLC法同时测定CYP450的3种同工酶特异性探针底物在SD大鼠肝微粒体内代谢产物生成量和原型探针底物降解量,判断酶亚型活性变化。分析柱Diamonsil C18 (150 mm×4.6 mm,5 μm),流速1.0 mL/min。CYP1A2代谢样品测定条件为甲醇(0.1%甲酸)(A)-水(0.1%甲酸)(B),0~5 min: 18%A,5~10 min: 18%~60%A,10~15 min: 60%A,检测波长为247 nm；CYP3A4代谢样品测定条件为甲醇(A)-水(0.02%甲酸)(B),0~11 min: 40%~60%A,检测波长为223 nm；CYP2E1代谢样品测定条件为甲醇(A)-水(B),0~10 min: 37%~75%A,检测波长为287 nm。结果 探针底物及其代谢产物在测定浓度范围内线性关系良好(r≥0.999 7),精密度RSD<6％(n=5),提取回收率83.2%～97.5%。SD大鼠连续注射给予盐酸头孢他美后,CYP3A4的活性与对照组比较差异有统计学意义(P<0.05),可能存在诱导作用；CYP1A2和CYP2E1的活性与对照组比较差异无统计学意义 (P>0.05)。结论 静注给予盐酸头孢他美能诱导SD大鼠肝微粒体CYP3A4,对CYP1A2和CYP2E1没有诱导或抑制作用。提示经CYP3A4 代谢的药物在临床上与注射用盐酸头孢他美合用时,可能存在潜在药物-药物相互作用。 |
| 关键词: 头孢他美 肝微粒体 细胞色素P450 CYP1A2 细胞色素P450 CYP3A4 细胞色素P450 CYP2E1 |
| DOI： |
| 投稿时间：2013-03-25修订日期：2013-06-06 |
| 基金项目:国家“重大新药创新”科技专项(2009ZX09301-011-07,2012ZX09303-011-002). |
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| Effects of cefetamet hydrochloride injection on activity of CYP1A2,CYP3A4 and CYP2E1 in liver microsomes of rats |
| LI Song1,2,3,TANG Yuan jun1,HE Jing yu4,YE Xiao lan5,YANG Peng4,LI Wei3*,FAN Guo rong1* |
(1. Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University & Key Laboratory of Shanghai Drug (Chinese Materia Medica) Metabolism Research, Shanghai 200433, China
2. Department of Urology GCP Office,Changhai Hospital,Second Military Medical University,Shanghai 200433,China
3. Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China
4. College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, Fujian, China
5. Department of Pharmaceutical Analysis, Guangdong Pharmaceutical University, Guangzhou 510000, Guangdong, China
*Corresponding author.) |
| Abstract: |
| Objective To study the effect of cefetamet hydrochloride injection on the activity of 3 kinds of cytochrome P450 (CYP450) isoforms (CYP1A2, CYP3A4 and CYP2E1) in rat liver microsomes. Methods The SD rats were randomly divided into two groups: control group and cefetamet hydrochloride (CH) group, with each group containing 3 male rats and 3 female rats. The CH group was injected with cefetamet hydrochloride into the tail vein at 50 mg/(kg·d), twice a day for 7 days. A HPLC method was used for simultaneous determination of the production of metabolites and the degradation of the prototype probe substrates of 3 kinds of CYP450 isoforms, so as to evaluate the activity of hepatic CYP450. The analytical column was Diamonsil C18 column (150 mm×4.6 mm, 5 μm), with the flow rate being 1.0 mL/min. The mobile phase consisted of methanol (0.1% formic acid) (A)-water (0.1% formic acid)(B), 0-5 min: 18%A, 5-10 min: 18%-60%A, 10-15 min: 60%A and detected at 247 nm for determination of CYP1A2 activities; methanol (A)-water (0.02% formic acid)(B), 0-11 min: 40%-60%A and detected at 223 nm for determination of CYP3A4 activities; and methanol (A)-water, 0-10 min: 37%-75%A and detected at 287 nm for determination of CYP2E1 activities. Results Probe substrates and their metabolites showed good linearity within the determining range (r≥0.999 7). The precision of the method was <6% (n=5) and extraction recoveries were 83.2%-97.5%. After 7-day injection of CH,CYP3A4 activities were significantly different between the two groups (P<0.05); CYP1A2 and CYP2E1 activities were not significantly different between the two groups (P>0.05). Conclusion CH injection can significantly induce hepatic microsome CYP3A4 expression in SD rats, but has no induction or inhibition effect on CYP1A2 and CYP2E1, indicating that potential drug-drug interaction might occur when CH injection is co-administered with drugs metabolized by CYP3A4. |
| Key words: cefetamet liver microsomes cytochrome P-450 CYP1A2 cytochrome P-450 CYP3A4 cytochrome P-450 CYP2E1 |
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