三种头孢类抗生素血浆样品分析方法的研究及其应用
|
摘要
为了分别测定血浆中3种头孢类抗生素，本文建立了一种简便的HPLC-UV法和两种专属、灵敏、快速的LC／MS／MS法，所建方法已被成功地应用于药物动力学研究。
一、HPLC-UV法测定人血浆中的头孢他美
头孢他美酯为一前体药物，口服吸收后迅速转化成活性形式头孢他美。因此本文建立了测定人血浆中头孢他美的高效液相色谱法，并用于中国受试者口服头孢他美酯后的体内药物动力学研究。血浆样品经0.5mol／l高氯酸沉淀蛋白后，以0.05mol／l磷酸二氢铵-乙腈-0.05mol／l磷酸(80:16:4,v／v)为流动相，流速1.2ml／min，乌拉地尔为内标，经Hypersil BDS C_(18)柱分离。该法线性范围为0.2-10.0μg／ml，定量下限为0.2μg／ml。20名受试者口服500mg头孢他美酯后主要药动学参数T_(max)为3.5±0.95h，C_(max)为6.78±2.12μg／ml，t_(1／2)为2.70±0.55h，AUC_(0-t)为40.8±12.5μg·h／ml。该方法操作简便、快速，可满足临床药物动力学研究。
二、LC／MS／MS法测定人血浆中的头孢泊肟
头孢泊肟是前药头孢泊肟酯的活性代谢物，血浆中检测不到原形药物。因此本文建立了测定人血浆中头孢泊肟的液相色谱-质谱-质谱联用法，并用于中国受试者口服头孢泊肟酯后的药物动力学研究。血浆样品经沉淀蛋白后，以乙腈-水-甲酸(70:30:1，v／v)为流动相，流速0.5ml／min，头孢他美为内标，采用Zorbax XDB-C_8柱分离，通过液相色谱-质谱-质谱，以选择反应监测(SRM)方式进行检测。定量分析时的离子反应分别为m／z 428→m／z 241(头孢泊肟)和m／z 398→m／z 241(头孢他美)。该法线性范围为0.05-8.0μg／ml，定量下限为0.05μg／ml。每个样
摘 要2
品的色谱分析时间仅为 3刀 min。18名受试者口服头抱泊脂酯（相当于头
抱泊厉 200 mg）后主要药动学参数几。为 26土 0．sib，Cm。为 2．75土
0．65卜g／nl，t；。为 2．27士 0．46 h，A UC。为 15 ＊土 3．5 pg·h／ml。该方法灵
敏度高，线性范围宽，操作简便、快速，适用于临床药物动力学研究。
．三、LCIMSfMS法测定人血浆中的头抱克躬
建立测定人血浆中头抱克胎的液相色谱一质谱一质谱联用法，并用于
中国受试者口服头抱克胎后的体内药物动力学研究。血浆样品经沉淀蛋
白后，以乙睛－水－甲酸＊：50：0．5，v／v）为流动相，流速 0．5二l／mi二，头
抱他美为内标，采用 Zorbax Extend—C；8柱分离，通过液相色谱一质谱一质
谱，以多反应监测 ＊删方式进行检测。定量分析时的离子反应分别
为m店壮4＋m店285（头抱克胎）和m店3％＋m店241（头抱他美）。该
法线性范围为 0刀25七刀 pg／inl，定量下限为 0刀25 pg／thl。每个样品的色
谱分析时间仅为 3刀 min。18名受试者口服 200 mg头抱克厉后主要药动
学参数几。为4．44土0．86 h，Cm。为2．73上0．79卜咖1，ilo为4．10士0．34
h，AUC。为 24．4土6．5 pg·hal。该方法灵敏度高，线性范围宽，操作简
便、快速，己成功地应用于头抱克脂临床药物动力学研究。
A selective HPLC-UV method and two sensitive and specific LC/MS/MS methods were developed to determine the cephalosporin levels in human plasma. The methods were successfully used in pharmacokinetic studies.
1. Determination of cefetamet in human plasma by high-performance liquid chromatography
Cefetamet pivoxil is a prodrug that is rapidly de-esterified after absorption to yield its active metabolite, cefetamet. So a selective high-performance liquid chromatographic method was developed for the determination of cefetamet levels in human plasma. Sample preparation involved protein precipitation with 0.5 mol/1 perchloric acid. Cefetamet and the internal standard, urapidil, were separated on a Hypersil BDS C18 column, using a mobile phase of 0.05 mol/1 phosphate buffer-acetonitrile-0.05 mol/1 phosphoric acid (80: 16: 4, v/v) at a flow-rate of 1.2 ml/min. The lower limit of quantification was 0.2 g/ml. The method was applicated to study the pharmacokinetics of 20 healthy volunteers after oral administration of 500 mg of cefetamet pivoxil. Mean peak plasma levels (Cmax) of 6.78 2.12 /ml and rmax of 3.5 0.95 h were observed. The mean t\a value of 2.70 0.55 h was obtained, AUC0-t was calculated to be 40.8 12.5 g-h/ml. The method was shown sensitive in the determination of cefetamet levels in plasma samples, and was successfully used in pharmacokinetics investigation of cefetamet pivoxil.
2. Determination of cefpodoxime in human plasma by liquid
Abstract
chromatography-tandem mass spectrometry
The prodrug cefepodoxime proxetil is the esterified form of cefpodoxime, and the parent compound can't be determined in plasma. So the objective of this investigation was to develop a sensitive and specific LC/MS/MS method for determination of cefpodoxime in human plasma and to investigate pharmacokinetics of single dose of cefpodoxime in healthy Chinese volunteers. Cefpodoxime and the internal standard cefetamet were deproteinated by acetonitrile, then separated on a Zorbax XDB-C8 column. The mobile phase consisted of acetonitrile-water-formic acid (70: 30: 1, v/v), at a flow-rate of 0.5 ml/min. A Finnigan TSQ tandem mass spectrometer equipped with ESI source was used as detector and was operated in the positive ion mode. Selected reaction monitoring (SRM) using the precursor - product ion combinations of m/z 428 - m/z 241 and m/z 398 - m/z 241 was used to quantify cefpodoxime and internal standard, respectively. The linear calibration curve was obtained in the concentration range of 0.5-8.0 g/ml. The limit of quantification was 0.5 g/ml. Each plasma sample was chromatographed within 3.0 min. The method was successfully used in the pharmacokinetic study for cefpodoxime proxetil. The main parameters obtained after an oral dose of 200 mg cefpodoxime proxetil to 18 Chinese volunteers were as follows: Cmin was found to be 2.75 0.65 (ig/ml, Tmax observed was 2.6 0.81 h , the value of t1/2 was 2.27 0.46 h, AUC0-t obtained was 15.6 3.5 g-h/ml. The method is proved to be specificity, speed, sensitivity and suitable for clinical investigation of cefpodoxime proxetil pharmacokinetics.
3. Determination of cefixime in human plasma by liquid chromatography-tandem mass spectrometry
A liquid chromato graphic-tandem mass spectrometric method was developed for the analysis of cefixime in human plasma. The analyte and
Abstract
precipitation of plasma proteins. The compounds were eluted isocratically on a Zobarx Extend-Cis column. LC/MS/MS in positive mode used pairs of ions at m/z of 454/285 for cefixime and 398/241 for the IS (cefetamet), respectively. The linear calibration curve of cefixime was over the range of 0.025 to 8.0 ng/ml with a lower limit of quantitation of 0.025 |ag/ml. The pharmacokinetics was investigated in 18 healthy volunteers after single dose 200 mg of cefixime. Cmax value was found to be 2.73 0.79 g/ml, Tmax was 4.44 0.86 h, plasma concentration declined with mean terminal half live (tin) of 4.10 0.34 h, the value of AUC0-t was obser
一、HPLC-UV法测定人血浆中的头孢他美
头孢他美酯为一前体药物，口服吸收后迅速转化成活性形式头孢他美。因此本文建立了测定人血浆中头孢他美的高效液相色谱法，并用于中国受试者口服头孢他美酯后的体内药物动力学研究。血浆样品经0.5mol／l高氯酸沉淀蛋白后，以0.05mol／l磷酸二氢铵-乙腈-0.05mol／l磷酸(80:16:4,v／v)为流动相，流速1.2ml／min，乌拉地尔为内标，经Hypersil BDS C_(18)柱分离。该法线性范围为0.2-10.0μg／ml，定量下限为0.2μg／ml。20名受试者口服500mg头孢他美酯后主要药动学参数T_(max)为3.5±0.95h，C_(max)为6.78±2.12μg／ml，t_(1／2)为2.70±0.55h，AUC_(0-t)为40.8±12.5μg·h／ml。该方法操作简便、快速，可满足临床药物动力学研究。
二、LC／MS／MS法测定人血浆中的头孢泊肟
头孢泊肟是前药头孢泊肟酯的活性代谢物，血浆中检测不到原形药物。因此本文建立了测定人血浆中头孢泊肟的液相色谱-质谱-质谱联用法，并用于中国受试者口服头孢泊肟酯后的药物动力学研究。血浆样品经沉淀蛋白后，以乙腈-水-甲酸(70:30:1，v／v)为流动相，流速0.5ml／min，头孢他美为内标，采用Zorbax XDB-C_8柱分离，通过液相色谱-质谱-质谱，以选择反应监测(SRM)方式进行检测。定量分析时的离子反应分别为m／z 428→m／z 241(头孢泊肟)和m／z 398→m／z 241(头孢他美)。该法线性范围为0.05-8.0μg／ml，定量下限为0.05μg／ml。每个样
摘 要2
品的色谱分析时间仅为 3刀 min。18名受试者口服头抱泊脂酯（相当于头
抱泊厉 200 mg）后主要药动学参数几。为 26土 0．sib，Cm。为 2．75土
0．65卜g／nl，t；。为 2．27士 0．46 h，A UC。为 15 ＊土 3．5 pg·h／ml。该方法灵
敏度高，线性范围宽，操作简便、快速，适用于临床药物动力学研究。
．三、LCIMSfMS法测定人血浆中的头抱克躬
建立测定人血浆中头抱克胎的液相色谱一质谱一质谱联用法，并用于
中国受试者口服头抱克胎后的体内药物动力学研究。血浆样品经沉淀蛋
白后，以乙睛－水－甲酸＊：50：0．5，v／v）为流动相，流速 0．5二l／mi二，头
抱他美为内标，采用 Zorbax Extend—C；8柱分离，通过液相色谱一质谱一质
谱，以多反应监测 ＊删方式进行检测。定量分析时的离子反应分别
为m店壮4＋m店285（头抱克胎）和m店3％＋m店241（头抱他美）。该
法线性范围为 0刀25七刀 pg／inl，定量下限为 0刀25 pg／thl。每个样品的色
谱分析时间仅为 3刀 min。18名受试者口服 200 mg头抱克厉后主要药动
学参数几。为4．44土0．86 h，Cm。为2．73上0．79卜咖1，ilo为4．10士0．34
h，AUC。为 24．4土6．5 pg·hal。该方法灵敏度高，线性范围宽，操作简
便、快速，己成功地应用于头抱克脂临床药物动力学研究。
A selective HPLC-UV method and two sensitive and specific LC/MS/MS methods were developed to determine the cephalosporin levels in human plasma. The methods were successfully used in pharmacokinetic studies.
1. Determination of cefetamet in human plasma by high-performance liquid chromatography
Cefetamet pivoxil is a prodrug that is rapidly de-esterified after absorption to yield its active metabolite, cefetamet. So a selective high-performance liquid chromatographic method was developed for the determination of cefetamet levels in human plasma. Sample preparation involved protein precipitation with 0.5 mol/1 perchloric acid. Cefetamet and the internal standard, urapidil, were separated on a Hypersil BDS C18 column, using a mobile phase of 0.05 mol/1 phosphate buffer-acetonitrile-0.05 mol/1 phosphoric acid (80: 16: 4, v/v) at a flow-rate of 1.2 ml/min. The lower limit of quantification was 0.2 g/ml. The method was applicated to study the pharmacokinetics of 20 healthy volunteers after oral administration of 500 mg of cefetamet pivoxil. Mean peak plasma levels (Cmax) of 6.78 2.12 /ml and rmax of 3.5 0.95 h were observed. The mean t\a value of 2.70 0.55 h was obtained, AUC0-t was calculated to be 40.8 12.5 g-h/ml. The method was shown sensitive in the determination of cefetamet levels in plasma samples, and was successfully used in pharmacokinetics investigation of cefetamet pivoxil.
2. Determination of cefpodoxime in human plasma by liquid
Abstract
chromatography-tandem mass spectrometry
The prodrug cefepodoxime proxetil is the esterified form of cefpodoxime, and the parent compound can't be determined in plasma. So the objective of this investigation was to develop a sensitive and specific LC/MS/MS method for determination of cefpodoxime in human plasma and to investigate pharmacokinetics of single dose of cefpodoxime in healthy Chinese volunteers. Cefpodoxime and the internal standard cefetamet were deproteinated by acetonitrile, then separated on a Zorbax XDB-C8 column. The mobile phase consisted of acetonitrile-water-formic acid (70: 30: 1, v/v), at a flow-rate of 0.5 ml/min. A Finnigan TSQ tandem mass spectrometer equipped with ESI source was used as detector and was operated in the positive ion mode. Selected reaction monitoring (SRM) using the precursor - product ion combinations of m/z 428 - m/z 241 and m/z 398 - m/z 241 was used to quantify cefpodoxime and internal standard, respectively. The linear calibration curve was obtained in the concentration range of 0.5-8.0 g/ml. The limit of quantification was 0.5 g/ml. Each plasma sample was chromatographed within 3.0 min. The method was successfully used in the pharmacokinetic study for cefpodoxime proxetil. The main parameters obtained after an oral dose of 200 mg cefpodoxime proxetil to 18 Chinese volunteers were as follows: Cmin was found to be 2.75 0.65 (ig/ml, Tmax observed was 2.6 0.81 h , the value of t1/2 was 2.27 0.46 h, AUC0-t obtained was 15.6 3.5 g-h/ml. The method is proved to be specificity, speed, sensitivity and suitable for clinical investigation of cefpodoxime proxetil pharmacokinetics.
3. Determination of cefixime in human plasma by liquid chromatography-tandem mass spectrometry
A liquid chromato graphic-tandem mass spectrometric method was developed for the analysis of cefixime in human plasma. The analyte and
Abstract
precipitation of plasma proteins. The compounds were eluted isocratically on a Zobarx Extend-Cis column. LC/MS/MS in positive mode used pairs of ions at m/z of 454/285 for cefixime and 398/241 for the IS (cefetamet), respectively. The linear calibration curve of cefixime was over the range of 0.025 to 8.0 ng/ml with a lower limit of quantitation of 0.025 |ag/ml. The pharmacokinetics was investigated in 18 healthy volunteers after single dose 200 mg of cefixime. Cmax value was found to be 2.73 0.79 g/ml, Tmax was 4.44 0.86 h, plasma concentration declined with mean terminal half live (tin) of 4.10 0.34 h, the value of AUC0-t was obser
引文
1．吴镭主编．药学科学前沿与发展方向．北京：中国医药科技出版社，2000，54-59，4-5．
2．李家泰主编．临床药理学．北京：人民卫生出版社，1992，355-356．
3．李发美主编．医药高效液相色谱技术．北京：人民卫生出版社，1999，3-8，23-37，19，92-96．
4．孙毓庆主编．现代色谱法及其在医药中的应用．北京：人民卫生出版社，1998，196-203．
5．施奈德 LR，格莱吉克 JK，柯克兰 JJ．实用高效液相色谱法的建立．中文版．北京：科学出版社，2000，5．
6. Covery TR, Lee ED, Bruins AP, Henion JD. Liquid Chromatography/Mass Spectrometry. Anal Chem. 1986, 58, 1451A-1461A.
7. Matsuo T, Seyama Y. Introduction to modern biological mass spectrometry. J Mass Spectrom. 2000, 35, 114-130.
8. Niessen WMA, Tinke AP. Liquid chromatography-mass spectrometry: general principles and instrumentation. J Chromatogr A. 1995, 703, 37-57.
9. Lopea LL, Yu X, Cui D, Davis MR. Research Methods & applications: Identification of drug metabolites in biological matrices by intelligent automated liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 1998, 12, 1756-1760.
10. Lee MS, Kerns EH. LC/MS applications in drug development. Mass Spectrom Rev. 1999, 18, 187-279.
11. Hoja H, Marquet P, Verneuil B. Liquid chromatography-mass spectrometry in analytical toxicology. J Anal Toxicol. 1997, 21, 116-126.
12. Brewer W, Henion J. Atmospheric pressure ionization LC/MS/MS techniques for drug disposition studies. J Pharm Sci. 1998, 67, 395-402.
13. Ikonomou MG, Blades AT, Kebarle P. Elctrospray-ion spray: A comparison of Mechanisms and performance. Anal Chem. 1991, 63, 1989-1998.
14. Fenn JB, Mann M, Meng CK, Wong SF. Electrospray ionization-principles and practice. Mass Spectrom Rev. 1990, 9, 37-70.
15. Gaskell SJ. Electrospray: principles and practice. J Mass Spectrom. 1997, 32,677-688.
16. Careri M, Mangia A, Musci M. Applications of liquid chromatography-mass spectrometry interfacing systems in food analysis: pesticide, drag and toxic substance residues. J Chromatogr A. 1996, 727, 153-184.
17. Huang EC, Wachs T, Conboy JJ. Atmospheric pressure ionization mass spectrometry. Anal chem. 1990, 62, 713A-725A.
18. Muck W. Quantitative analysis of pharmacokinetic study samples by liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). Pharmazie. 1999, 9, 639-644.
19．戴自英主编．临床抗菌药物学．北京：人民卫生出版社，1985，142．
20．徐叔云主编．临床药理学．第二版．北京：人民卫生出版社，1999，352．
21．陈福群．头孢菌素类药品的进展．中国药业，1999，8，61-62．
22．孙定人等主编．国家临床新药集．北京：中国医药卫生出版社，2001，557-558，577-578．
23．武向锋，许志强，郭玲．浅谈头孢菌素类抗生素．中国药业，1997，8，21-22．．
24．杨藻定主编．医用药理学．第三版．北京：人民卫生出版社，1997，801-802．
25．林志彬，金有豫主编．医用药理学基础．北京：世界图书出版公司，1998，328-330．
26．徐宝国．浅谈头孢菌素的构效与临床应用．镇江医学院院报．2000，10，568-570．
27．严宝霞主编．临床药学各论．北京：北京医科大学出版社，1999，329-333．
28. Bryson HM, Brogden RN. Cefetamet pivoxil, a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs. 1993, 45, 589-621.
29. Wyss R, Bucheli F. Determination of cefetamet and its orally active ester, cefetamet pivoxil, in biological fluids by high-performance liquid cheomatography. J Chromatogr. 1988, 430, 81-92.
30．阮邹荣，袁虹，孙凌等．盐酸头孢他美酯的药代动力学研究。中国临床药理学杂志．2000，16，301-303．
31. Koup JR, Dubach UC, Brandt R, et al. Parmacokinetics of cefetamet (Ro-8074) and cefetamet pivoxile (Ro 15-8075) after intravenous and oral doses in humans. Antimicrob Ag Chemother. 1988, 32, 573-579.
32. Tam YK, Kneer J, Dubach UC, et al. Pharmacikinetics of cefetamet pivoxil (Ro15-8075) with ascending oral doses in normal healthy volunteers. Antimicrob Ag Chemother. 1989, 33,957-959.
33. Hayton WL, Kneer J, Blouin KA, et al. Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with hepatic cirrhosis. Antimicrob Ag
Chemother. 1990, 34, 1318-1322.
34. Hayton WL, Walstad RA, Thurmann-Nielsen E, et al. Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in children. Antimicrob Ag Chemother. 1991, 35, 720-725.
35. Steckel K. Pharmacokinetics of intravenous cefetamet and oral cefetamet pivocil in human subjects. Drug Invest. 1991, 3,291-298.
36. Zimmerli W, Sansano S, Wittke B. Pharmacokinetics of cefetamet in plasma and skin blister fluid. Antimicrob Ag Chemother. 1996, 40, 102-104.
37．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．药物分析杂志．1996，16，343-346．
38. Shah VP, Midha KK, Hulse JD, et al. Bioanalytical methods validation — a revisit with a decade of progress. Pharm Res. 2000, 17, 1551-1557.
39．萧参，陈坚行．生物药剂分析方法的认证．中国药学杂志，1993，24，425-426．
40. Karnes HT, March C. Precision, accuracy and data acceptance criteria in biopharmaceutical analysis. Pharm Res, 1993, 10, 1420-1422.
41．国家药典委员会编．药物制剂人体生物利用度和生物等效性试验指导原则．见：中华人民共和国药典，2000年版二部，附录193-197．
42．曹晓梅，刘敏，卜一珊等．头孢他美酯片人体生物利用度研究．中国临床药理学杂志．2000，16，356-358．
43．谢静，宋丽丽，庄展辉．RP-HPLC法测定人血浆中的头孢他美酸的浓度．广东药学院学报．2001，17，48-49．
44．卢华，卢春来．反相高效液相色谱法测定血清中头孢他美．中国药房．2002，13，334-336．
45．李焕德，彭文兴，李阳等．头孢他美酯人体内药动学研究．中国药学杂志．2001，36，467-469．
46. Fulton B, Perry CM. Cefpodoxime proxetil: a review of its use in the management of bacterial infections in paediatric patients. Paediatr Drugs. 2001, 3, 137-158.
47. Frampton JE, Brogden RN, Langtry HD, et al. Cefpodoxime proxetil. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Drugs. 1992, 44, 889-917.
48. Hughes GS, Heald DL, Barker KB, et al. The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil. Clin Pharmacol Ther. 1989, 46, 674-685.
49. Borin MT, Forbes KK. Effect of food on absorption of cefpodoxime proxetil oral
suspension in adults. Antimicrob Ag Chemother. 1995, 39, 273-275.
50. Borin MT, Ferry JJ, Forbes KK, et al. Pharmacokinetics of cefpodoxime proxetil in healthy young and elderly volunteers. J Clin Pharmacol. 1994, 34, 774-781.
51．罗顺德，于星，尹武华等．头孢泊肟酯的体内过程．中国药学杂志．1996，31，110-112．
52. Borin MT, Hughes GS, Patel RK, et al. Pharmacokinetic and tolerance studies of cefpodoxime after single- and multiple-dose oral administration of cefpodoxime proxetil. J Clin Pharmacol. 1991, 31, 1137-1145.
53. Borin MT. A review of the pharmacokinetics of cefpodoxime proxetil. Drugs. 1991, 42 (Suppl), 13-21.
54. Camus F, Deslandes A, Harcouet L, et al. High-performance liquid chromatographic method for the determination of cefpodoxime levels in plasma and sinus mucosa. J Chromatogr B. 1994, 656, 383-388.
55. Steenwyk RC, Brewer JE, Royer ME, et al. Reversed-phase liqiud chromatographic determination of cefpodoxime in human plasma, J Liq Chromatogr. 1991, 14, 3641-3656.
56．赫广威，刘蕾，彭雯等．国产头孢泊肟酯片人体生物等效性．中国临床药理学杂志．2002；18(1)：53-56．
57. Bombardt PA, Cathcart KS, Bothwell BE, et al. Determination of cefpdoxime levels and cefpodoxime stability in human urine by direct injection HPLC with column-switching. J Liq Chromatogr. 1991, 14, 1729-1746.
58. Lovdahl MJ, Reher KE, Russlie HQ, et al. Determination of cefpodoxime levels in chinchilla middle ear fluid and plasma by high-performance liquid chromatography. J Chromatogr B. 1994, 653,227-232.
59. Molina F, Jehl F, Gilotin C, et al. Determination of the third generation oral cephalosporin cefpodoxime in biological fluids by high-performance liquid chromatography. J Chromatogr. 1991, 563,205-210.
60. Molina F, Jehl F, Gallion C, et al. Determination of the third generation oral cephalosporin cefpodoxime in biological fluids by high-speed high-performance liquid chromatography. J Chromatogr. 1991,563,205-210.
61．曾经泽．生物药物分析．北京：中国医药科技出版社，1990．
62. Debbia EA, Marchese A, Pesce A, et al. Parameters characterizing the in vitro activity of cefixime, a new oral broad spectrum cephalosporin, against respiratory and urinary pathogens. J Chemother. 1992, 4, 131-144.
63. Soussy CJ, Meyran M, Duval J. Antibacterial effect of cefixime. Presse Med. 1989, 18, 1546-1550.
64. Stone JW, Linong G, Andrews JM, et al. Cefixime, in-vitro activity, pharmacokinetics and tissue penetration. J Antimicrob Chemother. 1989, 23, 221-228.
65. Brittain DC, Scully BE, Hirose T, et al. The pharmacokinetic and bactericidal characteristics of oral cefixime. Clin Pharmacol Ther. 1985, 38, 590-594.
66. Leggett NJ, Caravaggio C, Rybak MJ. Cefixime. DICP. 1990, 24, 489-495.
67. Nakamura H, Iwai N. Pharmacokinetic studies on oral antibiotics in pediatrics. I. A pharmacokinetic study on cefixime in pediatrics. Jpn J Antibiot. 1991, 44, 964-978.
68. Barre J. Pharmacokinetic properties of cefixime. Presse Med. 1989, 18, 1578-1582.
69. Kees F, Naber KG. Pharmacokinetics of cefixime in volunteers and a literature comparison with the new ester prodrug cephalosporins. Infection. 1990, 18 (Suppl), S150-154.
70. Montay G, Le Liboux A, Thebault JJ, et al. Pharmacokinetics of cefixime in healthy volunteers after a single oral administration of 200 mg. Presse Med. 1989, 18, 1583-1586.
71. Faulkner RD, Bohaychuk W, Lanc RA, et al. Pharmacokinetics of cefixime in the young and elderly. J Antimicrob Chemother. 1988, 21,787-794.
72. Faulkner RD, Yacobi A, Barone JS, et al. Pharmacokinetic profile of cefixime in man. Pediatr Infect Dis J. 1987, 6, 963-970.
73. Faulkner RD, Bohaychuk W, Desjardins RE, et al. Pharmacokinetics of cefixime after once-a-day and twice-a-day dosing to steady state. J Clin Pharmacol. 1987, 27, 807-812.
74. Maeda H, Sako M, Fujii A, et al. Pharmacokinetics of cefixime in patients with impaired renal function. Jpn J Antibiot. 1986, 39, 2716-2720.
75. Guay DR, Meatherall RC, Harding GK, et al. Pharmacokinetics of cefixime (CL284,635; FK 027) in healthy subjects and patients with renal insufficiency. Antimicrob Agents Chemother. 1986, 30, 485-490.
76. Faulkner RD, Fernandez P, Lawrence G, et al. Absolute bioavailability of cefixime in man. J Clin Pharmacol. 1988, 28, 700-706.
77. Falkowski AJ, Look ZM, Noguchi H, et al. Determination of cefixime in biological samples by reversed-phase high-performance liquid chromatography. J Chromatogr. 1987, 422, 145-152.
78. Knoller J, Konig W, Schonfeld W, et al. Application of high-performance liquid chromatography of some antibiotics in clinical microbiology. J Chromatogr. 1988, 427, 257-267.
79. McAteer JA, Hiltke MF, Silber BM, et al. Liquid-chromatographic determination of five orally active cephalosporins--cefixime, cefaclor, cefadroxil, cephalexin, and cephradine -- in human serum. Clin Chem. 1987, 33, 1788-1790.
80. White LO, Reeves DS, Lovering AM, et al. HPLC assay of cefixime in serum and CSF. J Antimicrob Chemother. 1993, 1,450-451.
81．陈笑艳，栾燕，钟大放等，液相色谱-质谱-质谱联用法测定人血浆中氨氯地平．药学学报．2001，36，51-54．
82. Tenconi S, De Filippo L, Da Col L, et al. Electrospray mass spectrometry in the structural characterization of cephalosporins. J Mass Spectrom. 1999, 34,268-275.
2．李家泰主编．临床药理学．北京：人民卫生出版社，1992，355-356．
3．李发美主编．医药高效液相色谱技术．北京：人民卫生出版社，1999，3-8，23-37，19，92-96．
4．孙毓庆主编．现代色谱法及其在医药中的应用．北京：人民卫生出版社，1998，196-203．
5．施奈德 LR，格莱吉克 JK，柯克兰 JJ．实用高效液相色谱法的建立．中文版．北京：科学出版社，2000，5．
6. Covery TR, Lee ED, Bruins AP, Henion JD. Liquid Chromatography/Mass Spectrometry. Anal Chem. 1986, 58, 1451A-1461A.
7. Matsuo T, Seyama Y. Introduction to modern biological mass spectrometry. J Mass Spectrom. 2000, 35, 114-130.
8. Niessen WMA, Tinke AP. Liquid chromatography-mass spectrometry: general principles and instrumentation. J Chromatogr A. 1995, 703, 37-57.
9. Lopea LL, Yu X, Cui D, Davis MR. Research Methods & applications: Identification of drug metabolites in biological matrices by intelligent automated liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 1998, 12, 1756-1760.
10. Lee MS, Kerns EH. LC/MS applications in drug development. Mass Spectrom Rev. 1999, 18, 187-279.
11. Hoja H, Marquet P, Verneuil B. Liquid chromatography-mass spectrometry in analytical toxicology. J Anal Toxicol. 1997, 21, 116-126.
12. Brewer W, Henion J. Atmospheric pressure ionization LC/MS/MS techniques for drug disposition studies. J Pharm Sci. 1998, 67, 395-402.
13. Ikonomou MG, Blades AT, Kebarle P. Elctrospray-ion spray: A comparison of Mechanisms and performance. Anal Chem. 1991, 63, 1989-1998.
14. Fenn JB, Mann M, Meng CK, Wong SF. Electrospray ionization-principles and practice. Mass Spectrom Rev. 1990, 9, 37-70.
15. Gaskell SJ. Electrospray: principles and practice. J Mass Spectrom. 1997, 32,677-688.
16. Careri M, Mangia A, Musci M. Applications of liquid chromatography-mass spectrometry interfacing systems in food analysis: pesticide, drag and toxic substance residues. J Chromatogr A. 1996, 727, 153-184.
17. Huang EC, Wachs T, Conboy JJ. Atmospheric pressure ionization mass spectrometry. Anal chem. 1990, 62, 713A-725A.
18. Muck W. Quantitative analysis of pharmacokinetic study samples by liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). Pharmazie. 1999, 9, 639-644.
19．戴自英主编．临床抗菌药物学．北京：人民卫生出版社，1985，142．
20．徐叔云主编．临床药理学．第二版．北京：人民卫生出版社，1999，352．
21．陈福群．头孢菌素类药品的进展．中国药业，1999，8，61-62．
22．孙定人等主编．国家临床新药集．北京：中国医药卫生出版社，2001，557-558，577-578．
23．武向锋，许志强，郭玲．浅谈头孢菌素类抗生素．中国药业，1997，8，21-22．．
24．杨藻定主编．医用药理学．第三版．北京：人民卫生出版社，1997，801-802．
25．林志彬，金有豫主编．医用药理学基础．北京：世界图书出版公司，1998，328-330．
26．徐宝国．浅谈头孢菌素的构效与临床应用．镇江医学院院报．2000，10，568-570．
27．严宝霞主编．临床药学各论．北京：北京医科大学出版社，1999，329-333．
28. Bryson HM, Brogden RN. Cefetamet pivoxil, a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs. 1993, 45, 589-621.
29. Wyss R, Bucheli F. Determination of cefetamet and its orally active ester, cefetamet pivoxil, in biological fluids by high-performance liquid cheomatography. J Chromatogr. 1988, 430, 81-92.
30．阮邹荣，袁虹，孙凌等．盐酸头孢他美酯的药代动力学研究。中国临床药理学杂志．2000，16，301-303．
31. Koup JR, Dubach UC, Brandt R, et al. Parmacokinetics of cefetamet (Ro-8074) and cefetamet pivoxile (Ro 15-8075) after intravenous and oral doses in humans. Antimicrob Ag Chemother. 1988, 32, 573-579.
32. Tam YK, Kneer J, Dubach UC, et al. Pharmacikinetics of cefetamet pivoxil (Ro15-8075) with ascending oral doses in normal healthy volunteers. Antimicrob Ag Chemother. 1989, 33,957-959.
33. Hayton WL, Kneer J, Blouin KA, et al. Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with hepatic cirrhosis. Antimicrob Ag
Chemother. 1990, 34, 1318-1322.
34. Hayton WL, Walstad RA, Thurmann-Nielsen E, et al. Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in children. Antimicrob Ag Chemother. 1991, 35, 720-725.
35. Steckel K. Pharmacokinetics of intravenous cefetamet and oral cefetamet pivocil in human subjects. Drug Invest. 1991, 3,291-298.
36. Zimmerli W, Sansano S, Wittke B. Pharmacokinetics of cefetamet in plasma and skin blister fluid. Antimicrob Ag Chemother. 1996, 40, 102-104.
37．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．药物分析杂志．1996，16，343-346．
38. Shah VP, Midha KK, Hulse JD, et al. Bioanalytical methods validation — a revisit with a decade of progress. Pharm Res. 2000, 17, 1551-1557.
39．萧参，陈坚行．生物药剂分析方法的认证．中国药学杂志，1993，24，425-426．
40. Karnes HT, March C. Precision, accuracy and data acceptance criteria in biopharmaceutical analysis. Pharm Res, 1993, 10, 1420-1422.
41．国家药典委员会编．药物制剂人体生物利用度和生物等效性试验指导原则．见：中华人民共和国药典，2000年版二部，附录193-197．
42．曹晓梅，刘敏，卜一珊等．头孢他美酯片人体生物利用度研究．中国临床药理学杂志．2000，16，356-358．
43．谢静，宋丽丽，庄展辉．RP-HPLC法测定人血浆中的头孢他美酸的浓度．广东药学院学报．2001，17，48-49．
44．卢华，卢春来．反相高效液相色谱法测定血清中头孢他美．中国药房．2002，13，334-336．
45．李焕德，彭文兴，李阳等．头孢他美酯人体内药动学研究．中国药学杂志．2001，36，467-469．
46. Fulton B, Perry CM. Cefpodoxime proxetil: a review of its use in the management of bacterial infections in paediatric patients. Paediatr Drugs. 2001, 3, 137-158.
47. Frampton JE, Brogden RN, Langtry HD, et al. Cefpodoxime proxetil. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Drugs. 1992, 44, 889-917.
48. Hughes GS, Heald DL, Barker KB, et al. The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil. Clin Pharmacol Ther. 1989, 46, 674-685.
49. Borin MT, Forbes KK. Effect of food on absorption of cefpodoxime proxetil oral
suspension in adults. Antimicrob Ag Chemother. 1995, 39, 273-275.
50. Borin MT, Ferry JJ, Forbes KK, et al. Pharmacokinetics of cefpodoxime proxetil in healthy young and elderly volunteers. J Clin Pharmacol. 1994, 34, 774-781.
51．罗顺德，于星，尹武华等．头孢泊肟酯的体内过程．中国药学杂志．1996，31，110-112．
52. Borin MT, Hughes GS, Patel RK, et al. Pharmacokinetic and tolerance studies of cefpodoxime after single- and multiple-dose oral administration of cefpodoxime proxetil. J Clin Pharmacol. 1991, 31, 1137-1145.
53. Borin MT. A review of the pharmacokinetics of cefpodoxime proxetil. Drugs. 1991, 42 (Suppl), 13-21.
54. Camus F, Deslandes A, Harcouet L, et al. High-performance liquid chromatographic method for the determination of cefpodoxime levels in plasma and sinus mucosa. J Chromatogr B. 1994, 656, 383-388.
55. Steenwyk RC, Brewer JE, Royer ME, et al. Reversed-phase liqiud chromatographic determination of cefpodoxime in human plasma, J Liq Chromatogr. 1991, 14, 3641-3656.
56．赫广威，刘蕾，彭雯等．国产头孢泊肟酯片人体生物等效性．中国临床药理学杂志．2002；18(1)：53-56．
57. Bombardt PA, Cathcart KS, Bothwell BE, et al. Determination of cefpdoxime levels and cefpodoxime stability in human urine by direct injection HPLC with column-switching. J Liq Chromatogr. 1991, 14, 1729-1746.
58. Lovdahl MJ, Reher KE, Russlie HQ, et al. Determination of cefpodoxime levels in chinchilla middle ear fluid and plasma by high-performance liquid chromatography. J Chromatogr B. 1994, 653,227-232.
59. Molina F, Jehl F, Gilotin C, et al. Determination of the third generation oral cephalosporin cefpodoxime in biological fluids by high-performance liquid chromatography. J Chromatogr. 1991, 563,205-210.
60. Molina F, Jehl F, Gallion C, et al. Determination of the third generation oral cephalosporin cefpodoxime in biological fluids by high-speed high-performance liquid chromatography. J Chromatogr. 1991,563,205-210.
61．曾经泽．生物药物分析．北京：中国医药科技出版社，1990．
62. Debbia EA, Marchese A, Pesce A, et al. Parameters characterizing the in vitro activity of cefixime, a new oral broad spectrum cephalosporin, against respiratory and urinary pathogens. J Chemother. 1992, 4, 131-144.
63. Soussy CJ, Meyran M, Duval J. Antibacterial effect of cefixime. Presse Med. 1989, 18, 1546-1550.
64. Stone JW, Linong G, Andrews JM, et al. Cefixime, in-vitro activity, pharmacokinetics and tissue penetration. J Antimicrob Chemother. 1989, 23, 221-228.
65. Brittain DC, Scully BE, Hirose T, et al. The pharmacokinetic and bactericidal characteristics of oral cefixime. Clin Pharmacol Ther. 1985, 38, 590-594.
66. Leggett NJ, Caravaggio C, Rybak MJ. Cefixime. DICP. 1990, 24, 489-495.
67. Nakamura H, Iwai N. Pharmacokinetic studies on oral antibiotics in pediatrics. I. A pharmacokinetic study on cefixime in pediatrics. Jpn J Antibiot. 1991, 44, 964-978.
68. Barre J. Pharmacokinetic properties of cefixime. Presse Med. 1989, 18, 1578-1582.
69. Kees F, Naber KG. Pharmacokinetics of cefixime in volunteers and a literature comparison with the new ester prodrug cephalosporins. Infection. 1990, 18 (Suppl), S150-154.
70. Montay G, Le Liboux A, Thebault JJ, et al. Pharmacokinetics of cefixime in healthy volunteers after a single oral administration of 200 mg. Presse Med. 1989, 18, 1583-1586.
71. Faulkner RD, Bohaychuk W, Lanc RA, et al. Pharmacokinetics of cefixime in the young and elderly. J Antimicrob Chemother. 1988, 21,787-794.
72. Faulkner RD, Yacobi A, Barone JS, et al. Pharmacokinetic profile of cefixime in man. Pediatr Infect Dis J. 1987, 6, 963-970.
73. Faulkner RD, Bohaychuk W, Desjardins RE, et al. Pharmacokinetics of cefixime after once-a-day and twice-a-day dosing to steady state. J Clin Pharmacol. 1987, 27, 807-812.
74. Maeda H, Sako M, Fujii A, et al. Pharmacokinetics of cefixime in patients with impaired renal function. Jpn J Antibiot. 1986, 39, 2716-2720.
75. Guay DR, Meatherall RC, Harding GK, et al. Pharmacokinetics of cefixime (CL284,635; FK 027) in healthy subjects and patients with renal insufficiency. Antimicrob Agents Chemother. 1986, 30, 485-490.
76. Faulkner RD, Fernandez P, Lawrence G, et al. Absolute bioavailability of cefixime in man. J Clin Pharmacol. 1988, 28, 700-706.
77. Falkowski AJ, Look ZM, Noguchi H, et al. Determination of cefixime in biological samples by reversed-phase high-performance liquid chromatography. J Chromatogr. 1987, 422, 145-152.
78. Knoller J, Konig W, Schonfeld W, et al. Application of high-performance liquid chromatography of some antibiotics in clinical microbiology. J Chromatogr. 1988, 427, 257-267.
79. McAteer JA, Hiltke MF, Silber BM, et al. Liquid-chromatographic determination of five orally active cephalosporins--cefixime, cefaclor, cefadroxil, cephalexin, and cephradine -- in human serum. Clin Chem. 1987, 33, 1788-1790.
80. White LO, Reeves DS, Lovering AM, et al. HPLC assay of cefixime in serum and CSF. J Antimicrob Chemother. 1993, 1,450-451.
81．陈笑艳，栾燕，钟大放等，液相色谱-质谱-质谱联用法测定人血浆中氨氯地平．药学学报．2001，36，51-54．
82. Tenconi S, De Filippo L, Da Col L, et al. Electrospray mass spectrometry in the structural characterization of cephalosporins. J Mass Spectrom. 1999, 34,268-275.