给药后卡马西平大鼠血药浓度测定及其核磁共振代谢组学分析  

Determination of serum carbamazepine concentration and metabonomic analysis in rats

作　　者：蔡茁[1] 莫立乾[2] 关山越[3] 刘楚阳[2] 刘韵[2] 郭丹[2] 

机构地区：[1]解放军第458医院药剂科,广东广州510602 [2]南方医科大学南方医院药学部,广东广州510515 [3]中山大学测试中心,广东广州510275

出　　处：《南方医科大学学报》2014年第7期1025-1029,共5页Journal of Southern Medical University

基　　金：广州市白云区科技项目(2010-KZ-34)

摘　　要：目的采用基于核磁共振(NMR)的代谢组学技术分析卡马西平灌胃后对大鼠血清代谢组的影响。方法 24只健康雄性Wistar大鼠,随机分为4组:卡马西平高、中、低剂量组和正常对照组,每组6只。连续灌胃给药7 d后,麻醉后腹主动脉采血,于高效液相色谱仪中检测血清药物浓度,利用核磁共振技术测定血清1H NMR谱,进行模式识别分析,取肝肾组织进行病理学检查。结果卡马西平高、中、低3个剂量组稳态血药浓度分别为14.64±1.41、8.54±1.19、4.56±0.64μg·ml-1,卡马西平高剂量组肝脏有轻微肿胀,各组肾脏组织均无明显病变。血清中丙二胺、去氧皮质酮、脱氢胆固醇、甜菜碱、β-丙氨酸、胱硫醚、4-甲基-2-戊酮酸、肌酸含量下降,糖类、乳酸、琥珀酸、乙酰磷酸、己二酸含量升高。PCA主成分分析表明,给药组和对照组的代谢物存在明显差异,能够被区分开。卡马西平不同剂量组之间,代谢谱无种类的明显差异,只存在代谢物含量高低的不同。结论卡马西平对正常大鼠的代谢过程具有显著影响,这为卡马西平的临床用药监测和用药安全提供了依据。利用NMR技术对药物药效学和毒理学评价具有独特的优势和重要的价值。Objective To study the effects of carbamazepine on serum metabolic profiles in rats using nuclear magnetic resonance （NMR） spectroscopy. Methods Twenty-four healthy male Wistar rats were randomized into 4 groups （n=6） for daily intragastric administration of high-, medium-or low-dose carbamazepine or distilled water （control） for 7 days. Blood samples were collected from the abdominal aortic under anesthesia after the treatment to determine serum carbamazepine concentration using high-performance liquid chromatography. 1H nuclear magnetic resonance （1H NMR） spectra were acquired for pattern recognition analysis. Histopathological changes of the renal and liver tissues of the rats were also examined. Results Steady-state blood concentration of carbamazepine in high-, medium- and low-dose groups were 14.64 ± 1.41, 8.54 ± 1.19, and 4.56 ±0.64μg/ml, respectively. Slight liver swelling was found in high-dose group, but none of the groups showed renal pathologies. Compared with the control group, the high-dose carbamazepine group showed lowered serum concentrations of 1,3-diaminopropane, deoxycorticosterone, 7-dehydrocholesterol, betaine, beta-alanine, L-cystathionine, 4-methyl-2-oxovaleric acid, and creatine with increased levels of saccharides, lactate, succinic acid, acetyl phosphate, and adipic acid. Principal component analysis revealed significant differences of the metabolites between carbamazepine-treated groups and the control group. The metabolic profiles showed no differences in the kinds of metabolites although the concentrations of the metabolites varied between the carbamazepine groups. Conclusions Carbamazepine significantly affects metabolism in normal rats. This finding provides evidence for clinical drug monitoring and drug safety of carbamazepine. NMR technique has important values for pharmacodynamic and toxicological evaluation of drugs.

关 键 词：代谢组学 核磁共振 卡马西平 血药浓度 

分 类 号：R965[医药卫生—药理学]