测定人血浆中奥司他韦、伊曲康唑及二者活性代谢物
|
摘要
目的：建立专属、灵敏的LC／MS／MS法，测定人血浆中奥司他韦、伊曲康唑和二者活性代谢物并用于临床药动学研究和制剂生物等效性评价。
方法：同时测定人血浆中奥司他韦及其活性代谢物(Ro 64-0802)时，200μL，血浆样品经沉淀蛋白处理后，以甲醇：2mmol／L醋酸铵：甲酸(60：40：0.1，v／v／v)为流动相，Zorbax XDBC_(18)柱分离，采用API4000液相色谱-串联质谱仪，电喷雾电离源，正离子方式进行多反应监测(MRM)。用于定量分析的离子反应分别为m／z313→m／z225(奥司他韦)，m／z285→m／z197(Ro 64-0802)和m／z 256→m／z 167(内标，苯海拉明)。
同时测定人血浆中伊曲康唑和羟基伊曲康唑时，100μL血浆样品经沉淀蛋白处理后，以乙腈：水：甲酸(80：20：0.2，v／v／v)为流动相，Zorbax SB C_(18)柱分离，采用Thermo FinniganQuantum Ultra液相色谱-串联质谱仪，电喷雾电离源，以选择反应监测(SRM)方式进行正离子检测。用于定量分析的离子反应分别为m／z705→m／z(392+432)(伊曲康唑)，m／z721→m／z(392+408)(羟基伊曲康唑)和m／z 256→m／z 167(内标，苯海拉明)。
结果：测定人血浆中奥司他韦和Ro 64-0802的线性范围分别为0.435-435 ng／mL和0.740—740ng／mL：二者日内、日间精密度(RSD)均小于11.9％，准确度(RE)均在±3.8％以内。该方法已成功应用于磷酸奥司他韦制剂的临床生物等效性评价。测定人血浆中伊曲康唑及羟基伊曲康唑的线性范围均为1.00-1000ng／mL，定量下限均为1.00ng／mL。日内、日间精密度(RSD)均小于14.4％，准确度(RE)均在±6.3％以内。该方法已成功应用于伊曲康唑及羟基伊曲康唑的药物动力学研究。
结论：所建立的LC／MS／MS法专属、灵敏、简便、快速，可用于奥司他韦、伊曲康唑和二者活性代谢物的血药浓度测定并进行临床药动学研究及制剂的生物等效性评价。
Objective: To develop and validate rapid, sensitive and specific methods for quantitative analyses of oseltamivir and its active metabolite Ro 64-0802, itraconazole (ITZ) and its active metabolite hydroxyitraconazole (HIT) in plasma by liquid chromatographic-tandem mass spectrometry for pharmacokinetic studies.
Method: Oseltamivir, Ro 64-0802 and internal standard diphenhydramine were simply pretreated by protein precipitation using acetonitrile, and then analyzed on a Zorbax XDB C_(18) column. The mobile phase consisted of methanol-2 mM ammonium acetate-formic acid(60: 40: 0.1, v/v/v), at a flow-rate of 0.70 mL/min. An API 4000 tandem mass spectrometer equipped with turbospray ionization source was used as detector and was operated in the positive ion mode. Multiple reaction monitoring(MRM) using the precursor to product ion combinations of m/z 313→m/z 225, m/z 285→m/z 197 and m/z 265→m/z 167 was performed to quantify oseltamivir, Ro 64-0802 and the internal standard, respectively. ITZ, HIT and internal standard diphenhydramine were extracted from plasma using protein precipitation with acetonitrile, then separated on a Zorbax SB C_(18) column. The mobile phase consisted of acetonitrile-water-formic acid (80: 20: 0.2, v/v/v), at a flow-rate of 0.50 mL/min. A Thermo Finnigan TSQ Quantum Ultra tandem mass spectrometer equipped with electrospray ionization source was used as detector and was operated in the positive ion mode. Selected reaction monitoring using(SRM) the precursor to product ion combinations ofm/z 705→m/z (392+432), m/z 721→m/z (392 + 408) and m/z 256→m/z 167 was performed to quantify ITZ, HIT and the internal standard, respectively.
Results: The linear of oseltamivir and Ro 64-0802 curves were obtained in the concentration ranges of 0.435 - 435 ng/mL and 0.740 - 740 ng/mL respectively. The inter- and intra- day precision (RSD) were below 11.9 %, and the accuracy (RE) were within±3.8% calculated from QC samples. The method was successfully used in bioequivalence study of oseltamivir and Ro 64-0802 in human plasma after oral administration of 75 mg oseltamivir. The linear concentration ranges of calibration curves for ITZ and HIT were both 1.00 - 1000 ng/mL. The inter- and intra- day precision (RSD) were below 14.4 %, and the accuracy (RE) were within±6.3 % calculated from QC samples. The method was successfully used in pharmacokinetic studies of ITZ and HIT in human plasma after oral administration of 200 mg itraconazole.
Conclusion: The methods were successfully applied for the evaluation of the pharmacokinetics of oseltamivir, itraconazole and their metabolites.
方法：同时测定人血浆中奥司他韦及其活性代谢物(Ro 64-0802)时，200μL，血浆样品经沉淀蛋白处理后，以甲醇：2mmol／L醋酸铵：甲酸(60：40：0.1，v／v／v)为流动相，Zorbax XDBC_(18)柱分离，采用API4000液相色谱-串联质谱仪，电喷雾电离源，正离子方式进行多反应监测(MRM)。用于定量分析的离子反应分别为m／z313→m／z225(奥司他韦)，m／z285→m／z197(Ro 64-0802)和m／z 256→m／z 167(内标，苯海拉明)。
同时测定人血浆中伊曲康唑和羟基伊曲康唑时，100μL血浆样品经沉淀蛋白处理后，以乙腈：水：甲酸(80：20：0.2，v／v／v)为流动相，Zorbax SB C_(18)柱分离，采用Thermo FinniganQuantum Ultra液相色谱-串联质谱仪，电喷雾电离源，以选择反应监测(SRM)方式进行正离子检测。用于定量分析的离子反应分别为m／z705→m／z(392+432)(伊曲康唑)，m／z721→m／z(392+408)(羟基伊曲康唑)和m／z 256→m／z 167(内标，苯海拉明)。
结果：测定人血浆中奥司他韦和Ro 64-0802的线性范围分别为0.435-435 ng／mL和0.740—740ng／mL：二者日内、日间精密度(RSD)均小于11.9％，准确度(RE)均在±3.8％以内。该方法已成功应用于磷酸奥司他韦制剂的临床生物等效性评价。测定人血浆中伊曲康唑及羟基伊曲康唑的线性范围均为1.00-1000ng／mL，定量下限均为1.00ng／mL。日内、日间精密度(RSD)均小于14.4％，准确度(RE)均在±6.3％以内。该方法已成功应用于伊曲康唑及羟基伊曲康唑的药物动力学研究。
结论：所建立的LC／MS／MS法专属、灵敏、简便、快速，可用于奥司他韦、伊曲康唑和二者活性代谢物的血药浓度测定并进行临床药动学研究及制剂的生物等效性评价。
Objective: To develop and validate rapid, sensitive and specific methods for quantitative analyses of oseltamivir and its active metabolite Ro 64-0802, itraconazole (ITZ) and its active metabolite hydroxyitraconazole (HIT) in plasma by liquid chromatographic-tandem mass spectrometry for pharmacokinetic studies.
Method: Oseltamivir, Ro 64-0802 and internal standard diphenhydramine were simply pretreated by protein precipitation using acetonitrile, and then analyzed on a Zorbax XDB C_(18) column. The mobile phase consisted of methanol-2 mM ammonium acetate-formic acid(60: 40: 0.1, v/v/v), at a flow-rate of 0.70 mL/min. An API 4000 tandem mass spectrometer equipped with turbospray ionization source was used as detector and was operated in the positive ion mode. Multiple reaction monitoring(MRM) using the precursor to product ion combinations of m/z 313→m/z 225, m/z 285→m/z 197 and m/z 265→m/z 167 was performed to quantify oseltamivir, Ro 64-0802 and the internal standard, respectively. ITZ, HIT and internal standard diphenhydramine were extracted from plasma using protein precipitation with acetonitrile, then separated on a Zorbax SB C_(18) column. The mobile phase consisted of acetonitrile-water-formic acid (80: 20: 0.2, v/v/v), at a flow-rate of 0.50 mL/min. A Thermo Finnigan TSQ Quantum Ultra tandem mass spectrometer equipped with electrospray ionization source was used as detector and was operated in the positive ion mode. Selected reaction monitoring using(SRM) the precursor to product ion combinations ofm/z 705→m/z (392+432), m/z 721→m/z (392 + 408) and m/z 256→m/z 167 was performed to quantify ITZ, HIT and the internal standard, respectively.
Results: The linear of oseltamivir and Ro 64-0802 curves were obtained in the concentration ranges of 0.435 - 435 ng/mL and 0.740 - 740 ng/mL respectively. The inter- and intra- day precision (RSD) were below 11.9 %, and the accuracy (RE) were within±3.8% calculated from QC samples. The method was successfully used in bioequivalence study of oseltamivir and Ro 64-0802 in human plasma after oral administration of 75 mg oseltamivir. The linear concentration ranges of calibration curves for ITZ and HIT were both 1.00 - 1000 ng/mL. The inter- and intra- day precision (RSD) were below 14.4 %, and the accuracy (RE) were within±6.3 % calculated from QC samples. The method was successfully used in pharmacokinetic studies of ITZ and HIT in human plasma after oral administration of 200 mg itraconazole.
Conclusion: The methods were successfully applied for the evaluation of the pharmacokinetics of oseltamivir, itraconazole and their metabolites.
引文
[1] 程能能，陈斌艳，王永铭．新型口服抗流感药—奥司他韦．中国临床药学杂志，2002，11(1)：55-59．
[2] He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet, 1999, 37(6): 471-484.
[3] De Jong MD, Tran TT, Ttuong Hk,et al. Oseltamivir resistance during treatment of influenza A (HSN1) infection. N Engl J Med, 2005, 22;353(25): 2667-2672.
[4] 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．中华人民共和国药典，北京：化学工业出版社，2005年版二部，附录173-176．
[5] 陈佳，吴安．伊曲康唑治疗进展．中国皮肤性病学杂志，1998，12(6)：386-387．
[6] Beule K De. Itraconazole: pharmacology, clinical experience and future development. Antimicrob Agents Chemother, 1996, 6(3): 175-181.
[7] Conway SP, Etherington C, Peckham DG et al. Pharmacokinetics and safety of itraconazole in patients with cystic fibrosis. J Antimicrobial Chemotherapy, 2004, 53(5): 841-847.
[8] Summers KK, Hardin TC, Gore SJ et al. Therapeutic drug monitoring of systemic antifungal therapy. J Antimicrobial Chemotherapy, 1997, 40(6): 753-764.
[9] 钟大放主编．药物代谢．北京：中国医药科技出版社，1996，1-2．
[10] Sandrine S, Serge R, Jean-Luc V. Matrix effect in LC-ESI-MS and LC-APCI-MS with off-line and on-line extraction procedures, J Chromatogr A, 2004, 1058:61-66.
[11] Matuszewski BK. Standard line slopes as a measure of a relative matrix effect in quantitative HPLC-MS bioanalysis, J Chromatogr B, 2006, 830: 293-300.
[12] Fu Ⅰ, Wolf EJ, Matuszewski BK, Effect of the sample matrix on the determination of indinavir in human urine by HPLC with turbo ion spray tandem mass spectrometric detection, J Pharm. Biomed Anal, 1998, 18: 347-357.
[13] Pascoe R, Foley JP, Gusev, AI. Reduction in matrix-related signal suppression effecys in electrospray isonization mass spectrometry using on-line two-dimensional liquid chromatography. Anal Chem, 2001, 73: 6014-6023.
[14] Mallet CR, Lu Z, Mazzeo JR, A study of ion suppression effects in electrospray ionization from mobile phase additives and solid-phase extrats. Rapid Commun Mass Spectrom, 2004, 18: 49-58.
[15] 齐美玲．液相色谱—质谱法在生物样品药物定量分析中的基质效应．药物分析杂志，2005，25：476-479．
[16] Matuszewski BK, Constanzer ML, Chavez-Eng CM. Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS. Anal Chem, 2003, 75:3019-3030.
[17] Matuszewski BK, Constanzer ML, Chavez-Eng CM. Matrix effect in quantitative LC/MS/MS analyses of Biological fluids: a method for determination of finasteride in human plasma at pcogram per milliliter concentrations. Anal Chem, 1998, 70: 882-889.
[18] Mendel DB, Tai CY, Escarpe, et al. Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS4071 protects mice and ferrets against influenza infection. Antimicrob Agents Chemother, 1998, 42(3): 640-646.
[19] Li W, Escarpe PA, Eisenberg EJ,et al. Identification of GS 4104 as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS 4071. Antimicrob Agents Chemother,1998, 42(3): 647-653.
[20] Eisenberg EJ, Cundy KC. High-performance liquid chromatographic determination of GS4071, a potent inhibitor of influenza neuraminidase, in plasma by precolumn fluorescence derivadzafion with naphthalenedialdehyde. J Chromatogr B Biomed Sci Appl , 1998, 25;716(1-2): 267-273.
[21] 李雪宁，诸俊仁，王浩等．奥司他韦及其活性代谢物在健康人体的药动学．中国临床药学杂志．2002，11(5)：259-262．
[22] Wiltshire H, Wiltshire B, Citron A, et al. Development of a high-performance liquid chromatographic-mass spectrometric assay for the specific and sensitive quantification of Ro 64-0802, an anti-influenza drug, and its pro-drug, oseltamivir, in human and animal plasma and urine. J Chromatogr B Biomed Sci Appt, 2000, 745(2): 373-388.
[23] Shah VP, Midha KK, Findlay JW, et al. Bioanalytical method validation-a revisit with a decade of progress. Pharm Res, 2000, 17(12): 1551-1557.
[24] 《化学药物临床药代动力学研究技术指导原则》([H]GCLI-2)[S]．国家食品药品监督管理局．国食药监注2005．
[25] Srivatsan V, Dasgupta AK, Kale P. Simultaneous determination of itraconazole and hydroxyitraconazole in human plasma by high-performance liquid chromatography. J Chromatogr A, 2004, 1031(1-2): 307-313.
[26] Perfect JP, Savani DV, Durack DT. Comparison of itraconazole and flueonazole in treatment of cryptococcal meningitis anf candida pyelonephritis in rabbits. Antimicrob Agents Chemother; 1986; 29: 579-583.
[27] Law D, Moore CB, Denning. Bioassay for serum Itraconazole using Hydrixyitraeonazole standards. Antimicrob Agents Chemother; 1986; 26: 579-583.
[28] Breadmore MC, Prochazkova A, Theurillat R, et al. Determination of itraeonazole and hydroxyitraconazole in human serum and plasma by micellar electrokinetie chromatography. J ChromatogrA; 2003; 1014: 57-70.
[29] 陈钧，江文明，张敏等．HPLC测定人血浆中伊曲康唑及其代谢产物羟基伊曲康唑的浓度药物分析杂志．2005，25(7)：756-758．
[30] Redmann S, Charles BG. A rapid HPLC method with fluorometrie detection for determination of plasma itraconazole and hydroxy-itraconazole concentrations in cystic fibrosis children with allergic bronchopulmonary aspergillosis. Biomed Chromatogr, 2005,20(4): 343-348.
[31] Wong JW, Nisar UR, Yuen KH. Liquid chromatographic method for the determination of plasma itraconazole and its hydroxy metabolite in pharrnacokinetic/bioavailability studies. J Chromatogr B, 2003, 798(2): 355-360.
[32] Koks CH, Sparidana RW, Lucassen G, Crommentuyn KM, Beijnen JH. Selective high-performance liquid chromatographic assay for itraconazole and hydroxyitraconazole in plasma from human immunodeficiency virus-infected patients. J Chromatogr B, 2002, 767(1): 103-110.
[33] Sameer A1-Rawithi, Rajaa H, Ibrahim A1-Moshen. Expedient mierodetermination of itraconazole and hydroxyitraconazole in plasma by high-performance liquid chromatography with fluorescence detection. Ther Drug Monit, 2001, 23(4): 445-447.
[34] Carrier A, Parent J. Liquid chromatographic-mass spectrometric determination of itraconazole and its major metabolite, hydroxyitraconazole, in dog plasma. J Chromatogr B, 2000, 745(2): 413-420.
[35] Kousoulos C, Tsatsou G, Apostolou C, Dotsikas Y, Loukas YL. Development of a high-throughput method for the determination of itraconazole and its hydroxy metabolite in human plasma, employing automated liqud-liquid extraction based on 96-well format plates and LC/MS/MS. Anal Bioanal Chem, 2006, 384(1): 199-207.
[36] Muller C, Schafer P, Storzel M, Vogt S, Weinmann W. Ion suppression effects in liquid chromatography-electrospray-ionisation transport-region collision induced dissociation mass spectrometry with different serum extraction methods for systematic toxicological analysis with mass spectra libraries. J Chromatogr B, 2002, 773: 47-52.
[37] Shou WZ, Weng ND. Post-column infusion study of the 'dosing vehicle effect' in the liquid chromatography/tandem mass spectrometric analysis of discovery pharmacokinetic samples. Rapid Commun Mass Spectrom, 2003, 17: 589-597.
[38] Antignac J-P, Wasch K, Monteau F, et al. The ion suppression phenomenon in liquid chromatography-mass spectrometry and its consequences in the field of residue analysis. Analytica Chimica Acta, 2005, 529: 129-136.
[2] He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet, 1999, 37(6): 471-484.
[3] De Jong MD, Tran TT, Ttuong Hk,et al. Oseltamivir resistance during treatment of influenza A (HSN1) infection. N Engl J Med, 2005, 22;353(25): 2667-2672.
[4] 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．中华人民共和国药典，北京：化学工业出版社，2005年版二部，附录173-176．
[5] 陈佳，吴安．伊曲康唑治疗进展．中国皮肤性病学杂志，1998，12(6)：386-387．
[6] Beule K De. Itraconazole: pharmacology, clinical experience and future development. Antimicrob Agents Chemother, 1996, 6(3): 175-181.
[7] Conway SP, Etherington C, Peckham DG et al. Pharmacokinetics and safety of itraconazole in patients with cystic fibrosis. J Antimicrobial Chemotherapy, 2004, 53(5): 841-847.
[8] Summers KK, Hardin TC, Gore SJ et al. Therapeutic drug monitoring of systemic antifungal therapy. J Antimicrobial Chemotherapy, 1997, 40(6): 753-764.
[9] 钟大放主编．药物代谢．北京：中国医药科技出版社，1996，1-2．
[10] Sandrine S, Serge R, Jean-Luc V. Matrix effect in LC-ESI-MS and LC-APCI-MS with off-line and on-line extraction procedures, J Chromatogr A, 2004, 1058:61-66.
[11] Matuszewski BK. Standard line slopes as a measure of a relative matrix effect in quantitative HPLC-MS bioanalysis, J Chromatogr B, 2006, 830: 293-300.
[12] Fu Ⅰ, Wolf EJ, Matuszewski BK, Effect of the sample matrix on the determination of indinavir in human urine by HPLC with turbo ion spray tandem mass spectrometric detection, J Pharm. Biomed Anal, 1998, 18: 347-357.
[13] Pascoe R, Foley JP, Gusev, AI. Reduction in matrix-related signal suppression effecys in electrospray isonization mass spectrometry using on-line two-dimensional liquid chromatography. Anal Chem, 2001, 73: 6014-6023.
[14] Mallet CR, Lu Z, Mazzeo JR, A study of ion suppression effects in electrospray ionization from mobile phase additives and solid-phase extrats. Rapid Commun Mass Spectrom, 2004, 18: 49-58.
[15] 齐美玲．液相色谱—质谱法在生物样品药物定量分析中的基质效应．药物分析杂志，2005，25：476-479．
[16] Matuszewski BK, Constanzer ML, Chavez-Eng CM. Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS. Anal Chem, 2003, 75:3019-3030.
[17] Matuszewski BK, Constanzer ML, Chavez-Eng CM. Matrix effect in quantitative LC/MS/MS analyses of Biological fluids: a method for determination of finasteride in human plasma at pcogram per milliliter concentrations. Anal Chem, 1998, 70: 882-889.
[18] Mendel DB, Tai CY, Escarpe, et al. Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS4071 protects mice and ferrets against influenza infection. Antimicrob Agents Chemother, 1998, 42(3): 640-646.
[19] Li W, Escarpe PA, Eisenberg EJ,et al. Identification of GS 4104 as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS 4071. Antimicrob Agents Chemother,1998, 42(3): 647-653.
[20] Eisenberg EJ, Cundy KC. High-performance liquid chromatographic determination of GS4071, a potent inhibitor of influenza neuraminidase, in plasma by precolumn fluorescence derivadzafion with naphthalenedialdehyde. J Chromatogr B Biomed Sci Appl , 1998, 25;716(1-2): 267-273.
[21] 李雪宁，诸俊仁，王浩等．奥司他韦及其活性代谢物在健康人体的药动学．中国临床药学杂志．2002，11(5)：259-262．
[22] Wiltshire H, Wiltshire B, Citron A, et al. Development of a high-performance liquid chromatographic-mass spectrometric assay for the specific and sensitive quantification of Ro 64-0802, an anti-influenza drug, and its pro-drug, oseltamivir, in human and animal plasma and urine. J Chromatogr B Biomed Sci Appt, 2000, 745(2): 373-388.
[23] Shah VP, Midha KK, Findlay JW, et al. Bioanalytical method validation-a revisit with a decade of progress. Pharm Res, 2000, 17(12): 1551-1557.
[24] 《化学药物临床药代动力学研究技术指导原则》([H]GCLI-2)[S]．国家食品药品监督管理局．国食药监注2005．
[25] Srivatsan V, Dasgupta AK, Kale P. Simultaneous determination of itraconazole and hydroxyitraconazole in human plasma by high-performance liquid chromatography. J Chromatogr A, 2004, 1031(1-2): 307-313.
[26] Perfect JP, Savani DV, Durack DT. Comparison of itraconazole and flueonazole in treatment of cryptococcal meningitis anf candida pyelonephritis in rabbits. Antimicrob Agents Chemother; 1986; 29: 579-583.
[27] Law D, Moore CB, Denning. Bioassay for serum Itraconazole using Hydrixyitraeonazole standards. Antimicrob Agents Chemother; 1986; 26: 579-583.
[28] Breadmore MC, Prochazkova A, Theurillat R, et al. Determination of itraeonazole and hydroxyitraconazole in human serum and plasma by micellar electrokinetie chromatography. J ChromatogrA; 2003; 1014: 57-70.
[29] 陈钧，江文明，张敏等．HPLC测定人血浆中伊曲康唑及其代谢产物羟基伊曲康唑的浓度药物分析杂志．2005，25(7)：756-758．
[30] Redmann S, Charles BG. A rapid HPLC method with fluorometrie detection for determination of plasma itraconazole and hydroxy-itraconazole concentrations in cystic fibrosis children with allergic bronchopulmonary aspergillosis. Biomed Chromatogr, 2005,20(4): 343-348.
[31] Wong JW, Nisar UR, Yuen KH. Liquid chromatographic method for the determination of plasma itraconazole and its hydroxy metabolite in pharrnacokinetic/bioavailability studies. J Chromatogr B, 2003, 798(2): 355-360.
[32] Koks CH, Sparidana RW, Lucassen G, Crommentuyn KM, Beijnen JH. Selective high-performance liquid chromatographic assay for itraconazole and hydroxyitraconazole in plasma from human immunodeficiency virus-infected patients. J Chromatogr B, 2002, 767(1): 103-110.
[33] Sameer A1-Rawithi, Rajaa H, Ibrahim A1-Moshen. Expedient mierodetermination of itraconazole and hydroxyitraconazole in plasma by high-performance liquid chromatography with fluorescence detection. Ther Drug Monit, 2001, 23(4): 445-447.
[34] Carrier A, Parent J. Liquid chromatographic-mass spectrometric determination of itraconazole and its major metabolite, hydroxyitraconazole, in dog plasma. J Chromatogr B, 2000, 745(2): 413-420.
[35] Kousoulos C, Tsatsou G, Apostolou C, Dotsikas Y, Loukas YL. Development of a high-throughput method for the determination of itraconazole and its hydroxy metabolite in human plasma, employing automated liqud-liquid extraction based on 96-well format plates and LC/MS/MS. Anal Bioanal Chem, 2006, 384(1): 199-207.
[36] Muller C, Schafer P, Storzel M, Vogt S, Weinmann W. Ion suppression effects in liquid chromatography-electrospray-ionisation transport-region collision induced dissociation mass spectrometry with different serum extraction methods for systematic toxicological analysis with mass spectra libraries. J Chromatogr B, 2002, 773: 47-52.
[37] Shou WZ, Weng ND. Post-column infusion study of the 'dosing vehicle effect' in the liquid chromatography/tandem mass spectrometric analysis of discovery pharmacokinetic samples. Rapid Commun Mass Spectrom, 2003, 17: 589-597.
[38] Antignac J-P, Wasch K, Monteau F, et al. The ion suppression phenomenon in liquid chromatography-mass spectrometry and its consequences in the field of residue analysis. Analytica Chimica Acta, 2005, 529: 129-136.