盐酸多柔比星脂质体注射液大鼠体内药动学及组织分布的性别差异研究
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摘要
目的建立色谱-质谱联用方法测定大鼠血浆及组织中多柔比星浓度,用于盐酸多柔比星脂质体注射液大鼠体内药动学及组织分布性别差异研究。方法雌、雄两组大鼠经静脉给予盐酸多柔比星脂质体注射液3.0 mg/kg,采用LC-MS/MS法分别测定血浆、心、肝、脾、肺、肾、大肠、小肠、胃、肌肉和骨髓组织中多柔比星质量浓度,应用DAS2.0软件统计矩模型计算主要药动学参数。采用SPSS 20软件对药动学参数及组织中多柔比星的浓度分别进行独立样本t检验。结果给药后雌、雄两组大鼠的主要药动学参数t_(1/2)、k_e、ρ_(max)、AUC_(0-t)、AUC_(0-∞)、MRT_(0-t)、MRT_(0-∞)和CL均无显著性差异;组织分布结果显示,雌、雄两组大鼠给药后5 min的骨髓组织,给药后24 h的肌肉和肝组织,给药后72 h的肝组织以及给药后120 h的小肠和肺组织中多柔比星含量均存在显著性差异(P<0.05),其余时间点各组织均无显著性差异。结论大鼠静脉注射给予盐酸多柔比星脂质体注射液后药动学行为无显著性的性别差异,而药物在骨髓、肌肉、肝、小肠和肺组织中分布存在显著性的性别差异。
Objective To establish an LC-MS/MS method for determination of the concentration of doxorubicin in rat plasma and tissues. The method was used to study gender difference pharmacokinetics and tissue distribution of doxorubicin hydrochloride liposome injection in rat. Methods Female and male rats were given doxorubicin hydrochloride liposome injection( 3. 0 mg·kg~(-1)) by intravenous injection. The amounts of doxorubicin in plasma,heart,liver,spleen,lung,kidney,large intestine,small intestine,muscle,bone medulla and gastric tissues were determined by the validated LC-MS/MS method. The main pharmacokinetic parameters of doxorubicin were calculated using DAS2. 0 software. Gender differences in pharmacokinetics and tissue distribution in rat were analyzed by SPSS 20 with independent sample t test.Results The main pharmacokinetic parameters,including t_(1/2),k_e,ρ_(max),AUC_(0-t),AUC_(0-∞),MRT_(0-t),MRT_(0-∞) and CL,did not showsignificant difference between male and female rats. Gender difference of the amount of doxorubicin was observed at 5 min in bone medulla,at 24 h in muscle and hepar,at 72 h in hepar and at 120 h in small intestine and lung. Conclusion No significant gender difference can be found in the pharmacokinetic profile of doxorubicin in rat after a liposomal injection. The distribution of doxorubicin in a fewtissues seemed gender-dependent.
Objective To establish an LC-MS/MS method for determination of the concentration of doxorubicin in rat plasma and tissues. The method was used to study gender difference pharmacokinetics and tissue distribution of doxorubicin hydrochloride liposome injection in rat. Methods Female and male rats were given doxorubicin hydrochloride liposome injection( 3. 0 mg·kg~(-1)) by intravenous injection. The amounts of doxorubicin in plasma,heart,liver,spleen,lung,kidney,large intestine,small intestine,muscle,bone medulla and gastric tissues were determined by the validated LC-MS/MS method. The main pharmacokinetic parameters of doxorubicin were calculated using DAS2. 0 software. Gender differences in pharmacokinetics and tissue distribution in rat were analyzed by SPSS 20 with independent sample t test.Results The main pharmacokinetic parameters,including t_(1/2),k_e,ρ_(max),AUC_(0-t),AUC_(0-∞),MRT_(0-t),MRT_(0-∞) and CL,did not showsignificant difference between male and female rats. Gender difference of the amount of doxorubicin was observed at 5 min in bone medulla,at 24 h in muscle and hepar,at 72 h in hepar and at 120 h in small intestine and lung. Conclusion No significant gender difference can be found in the pharmacokinetic profile of doxorubicin in rat after a liposomal injection. The distribution of doxorubicin in a fewtissues seemed gender-dependent.
引文
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[14]孙习鹏,万丽丽,徐志儒,等.高效液相色谱法测定大鼠血浆及组织中多柔比星含量[J].中国药物应用与监测,2010,7(4):211-215.
[15]MA W,WANG J,GUO Q,et al.Simultaneous determination of doxorubicin and curcumin in rat plasma by LC-M S/M S and its application to pharmacokinetic study[J].Journal of Pharmaceutical&Biomedical Analysis,2015,111:215-221.
[16]方罗,范云,罗吕宏,等.聚乙二醇修饰的多柔比星脂质体在我国肿瘤患者体内的药动学研究[J].中国药学杂志,2012,47(3):223-228.
[2]DOROSHOW J H,TALLENT C,SCHECHTER J E.Ultrastructural features of Adriamycin-induced skeletal and cardiac muscle toxicity[J].American Journal of Pathology,1985,118(2):288-297.
[3]TAKEMURA G,FUJIWARA H.Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management.[J].Progress in Cardiovascular Diseases,2007,49(5):330-352.
[4]张文萍,甘梦月,马妍妮,等.LC-MS/MS法测定大鼠血浆中阿霉素的药物浓度及应用[J].中国医药导报,2014(35):55-59.
[5]XU L,WANG W,SHENG Y C,et al.Pharmacokinetics and its relation to toxicity of pegylated-liposomal doxorubicin in chinese patients with breast tumours[J].Journal of Clinical Pharmacy&Therapeutics,2010,35(5):593-601.
[6]张宁.仿制盐酸多柔比星脂质体注射液药学技术要求解析[J].中国新药杂志,2014(8):896-900.
[7]DOBBS N A,TWELVES C J,GILLIES H,et al.Gender affects doxorubicin pharmacokinetics in patients with normal liver biochemistry[J].Cancer Chemotherapy and Pharmacology,1995,36(6):473-476.
[8]郭真真.输注阿霉素患者的预期性胃肠道反应状况及相关因素研究[D].北京:中国人民解放军医学院,2012.
[9]钟大放.以加权最小二乘法建立生物分析标准曲线的若干问题[J].药物分析杂志,1996(5):343-346.
[10]范健,文旭,缪玉山,等.脂质体阿霉素与游离阿霉素在大鼠体内药代动力学[J].中国药科大学学报,2001,32(5):354-358.
[11]熊雯,蒋心惠,张丹.盐酸阿霉素及其脂质体在大鼠体内的相关药动学参数比较[J].华西药学杂志,2004,19(2):97-99.
[12]秦燕,徐智儒,王向伟,等.PEG化脂质体多柔比星在动物体内的药动学及组织分布[J].中国医药工业杂志,2009,40(8):596-599.
[13]龚连生,曾雅娟,张阳德,等.阿霉素纳米脂质体大鼠体内的药动学研究[J].中国现代医学杂志,2010,20(1):9-12.
[14]孙习鹏,万丽丽,徐志儒,等.高效液相色谱法测定大鼠血浆及组织中多柔比星含量[J].中国药物应用与监测,2010,7(4):211-215.
[15]MA W,WANG J,GUO Q,et al.Simultaneous determination of doxorubicin and curcumin in rat plasma by LC-M S/M S and its application to pharmacokinetic study[J].Journal of Pharmaceutical&Biomedical Analysis,2015,111:215-221.
[16]方罗,范云,罗吕宏,等.聚乙二醇修饰的多柔比星脂质体在我国肿瘤患者体内的药动学研究[J].中国药学杂志,2012,47(3):223-228.
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