罗格列酮在大鼠体内药动学及组织分布研究

张凌红; 段雅乐; 李于博; 万学梅; 赵政

罗格列酮在大鼠体内药动学及组织分布研究

1.
华东师范大学脑功能基因组学教育部及上海市重点实验室,上海 200062

详细信息

中图分类号: R965
计量
- 文章访问数: 2151
- HTML全文浏览量: 30
- PDF下载量: 1882
- 被引次数: 0
出版历程
- 收稿日期: 2010-05-01
- 修回日期: 2010-08-01
- 刊出日期: 2011-07-05

Pharmacokinetics and tissues distribution of rosiglitazone in rats

1.
Key Laboratories of MOE and STCSM, Institute of Brain Functional Genomics, East China Normal University， Shanghai 200062, China

摘要

摘要: 建立并验证一个简单和快速的血浆中罗格列酮RP-HPLC分析方法和提取方法，并将该法应用于罗格列酮体内药动学和组织分布研究.在大鼠给药前和给药后0.083, 0.25, 0.50, 1, 2, 3, 4, 6, 8, 10和24 h通过尾静脉采集血样检测，并检测给药1 h后各组织的罗格列酮的分布情况.给药后1 h，采集大鼠脑脊液，检测脑脊液内罗格列酮是否存在. 结果显示，大鼠灌胃给药3 mg/kg时，AUC(0-)为（1 574.419332.731） mgminL-1，Tmax为（4010） min，CL/F为0.002 Lmin-1kg-1，t1/2为（150.31444.209） min，Cmax为（6.9740.877）mg/L.给药1 h后，各个组织均有分布.罗格列酮能够透过血脑屏障，给药后1 h，通过率为0.004 5%.由此得出结论，罗格列酮在大鼠体内吸收迅速，分布广泛，且能够通过血脑屏障.
- 罗格列酮 /
- 反相高效液相色谱 /
- 药代动力学 /
- 组织分布 /
- 脑脊液
Abstract: A simple, rapid and selective HPLC method was developed and validated to determinate rosiglitazone in rat plasma, tissues and cerebrospinal fluid. Samples were prepared, with a higher extraction recovery (96.72% in plasma， 95.63% in tissues and 90.67% in cerebrospinal fluid), based on a simple methanol protein precipitation. Assay of rosiglitazone was achieved on a reversed-phase C18 column (250 mm 4.6 mm, 5 m) with a mobile phase consisting of acetonitrile and 20 mmol/L ammonium acetate pH 6.0 (53∶47, v/v) at a flow rate of 0.6 mL/min. The method was applied to study pharmacokinetics, distribution of rosiglitazone in rats after a single intragastric administration. The rosiglitazone was rapidly absorbed (Tmax 0.5～1 h) with an elimination half-life of 2.5 hours. The highest levels of the drug were observed in liver and fat while the lowest levels in the brain and spleen. The method was also used for the determination of rosiglitazone in cerebrospinal fluid. The result showed that rosiglitazone can be detected in cerebrospinal fluid, thus providing direct evidence that rosiglitazone can permeate cross blood brain barrier.
- rosiglitazone /
- HPLC-UV /
- pharmacokinetics /
- tissues distribution /
- cerebrospinal fluid

HTML全文

参考文献(1)

[1]

［1］ DAY C. Thiazolidinediones: a new class of antidiabetic drugs［J］. Diabet Med, 1999, 16(3): 179-192.

［2］ TONTONOZ P, HU E, SPIEGELMAN B M. Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor gamma［J］. Curr Opin Genet Dev, 1995, 5(5): 571-576.

［3］ ELDERSHAW T P, RATTIGAN S, CAWTHORNE M A, et al. Treatment with the thiazolidinedione (BRL 49653) decreases insulin resistance in obese Zucker hindlimb［J］. Horm Metab Res, 1995, 27(4): 169-172.

［4］ WATSON G S, CHOLERTON B A, REGER M A, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study［J］. Am J Geriat Psychiat, 2005, 13(11): 950-958.

［5］ RISNER M E, SAUNDERS A M, ALTMAN J F, et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease［J］. Pharmacogenomics J, 2006, 6(4): 246-254.

［6］ ESCRIBANO L, SIMON A M, PEREZ-MEDIAVILLA A, et al. Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer's disease mouse model［J］. Biochem Biophys Res Commun, 2009, 379(2): 406-410.

［7］ PEDERSEN W A, MCMILLAN P J, KULSTAD J J, et al. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice［J］. Exp Neurol, 2006, 199(2): 265-273.

［8］ XUE B, KAHN B B. AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissues［J］. J Physiol, 2006, 574(Pt 1): 73-83.

［9］ KIM M S, LEE K U. Role of hypothalamic 5′-AMP-activated protein kinase in the regulation of food intake and energy homeostasis［J］. J Mol Med, 2005, 83(7): 514-520.

［10］ FRYER L G, PARBU-PATEL A, CARLING D. The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways［J］. J Biol Chem, 2002, 277(28): 25226-25232.

［11］ TURNLEY A M, STAPLETON D, MANN R J, et al. Cellular distribution and developmental expression of AMP-activated protein kinase isoforms in mouse central nervous system［J］. J Neurochem, 1999, 72(4): 1707-1716.

［12］ FESTUCCIA W T, OZTEZCAN S, LAPLANTE M, et al. Peroxisome proliferator-activated receptor-gamma-mediated positive energy balance in the rat is associated with reduced sympathetic drive to adipose tissues and thyroid status［J］. Endocrinology, 2008, 149(5): 2121-2130.

［13］ LANDRETH G. PPARgamma agonists as new therapeutic agents for the treatment of Alzheimer's disease［J］. Exp Neurol, 2006, 199(2): 245-248.

［14］ KANG X, WANG F, XIE Z, et al. A high performance liquid chromatography method for simultaneous determination of rosiglitazone and gemfibrozil in human plasma［J］. J Chromatogr B Analyt Technol Biomed Life Sci, 2009, 877(7): 645-648.

［15］ KOLTE B L, RAUT B B, DEO A A, et al. Liquid chromatographic method for the determination of rosiglitazone in human plasma［J］. J Chromatogr B Analyt Technol Biomed Life Sci, 2003, 788(1): 37-44.

［16］ MUXLOW A M, FOWLES S, RUSSELL P. Automated high-performance liquid chromatography method for the determination of rosiglitazone in human plasma［J］. J Chromatogr B Biomed Sci Appl, 2001, 752(1): 77-84.

［17］ NIROGI R, KANDIKERE V, MUDIGONDA K, et al. A simple and rapid method to collect the cerebrospinal fluid of rats and its application for the assessment of drug penetration into the central nervous system［J］. J Neurosci Methods, 2009, 178(1): 116-119.

［18］ LAI Y L, SMITH P M, LAMM W J, et al. Sampling and analysis of cerebrospinal fluid for chronic studies in awake rats［J］. J Appl Physiol,1983, 54(6): 1754-1757.

［19］ HRUSKA M W, FRYE R F. Simplified method for determination of rosiglitazone in human plasma［J］. J Chromatogr B Analyt Technol Biomed Life Sci, 2004, 803(2): 317-320.

［20］ ZHANG L, TIAN Y, ZHANG Z, et al. Simultaneous determination of metformin and rosiglitazone in human plasma by liquid chromatography/tandem mass spectrometry with electrospray ionization: application to a pharmacokinetic study［J］. J Chromatogr B Analyt Technol Biomed Life Sci, 2007, 854(1-2): 91-98.

［21］ FREED M I, ALLEN A, JORKASKY D K, et al. Systemic exposure to rosiglitazone is unaltered by food［J］. Eur J Clin Pharmacol, 1999, 55(1): 53-56.

［22］ COX P J, RYAN D A, HOLLIS F J, et al. Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans［J］. Drug Metab Dispos, 2000, 28(7): 772-780.

［23］ BALDWIN S J, CLARKE S E, CHENERY R J. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone［J］. Br J Clin Pharmacol, 1999, 48(3): 424-432.

［24］ SARRUF D A, YU F, NGUYEN H T, et al. Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis［J］. Endocrinology, 2009, 150(2): 707-712.

施引文献

资源附件(0)

访问统计