High Performance Liquid Chromatography Coupling with Photo-diode Array Detector Method for Monitoring Voriconazole and Its Main Metabolite N-oxidized Voriconazole and Its Application to Medication Guidance for Childhood Leukemia
LUO Xing-xian, HUANG Lin, LI Tai-feng, HU Lei, LIU Xue-mei, XUE Xue-cai, ZHANG Hai-ying, CHEN Yue, FENG Wan-yu*
Department of Pharmacy, Peking University People′s Hospital, Beijing 100044, China
Abstract：OBJECTIVE To establish a method for simultaneous determination of voriconazole and its main metabolite N-oxidized voriconazole in blood, and monitor the levels of voriconazole and N-oxidized voriconazole in leukemia children aged 2-12 years. METHODS Agilent ZORBAX SB-C18 column (4.6 mm×250 mm,5 μm) was used, and the mobile phase was acetonitrile, methanol and ammonium acetate buffer (10 mmol·L-1, pH adjusted with acetic acid to 3.0)=27∶23∶50, the flow rate was 1 mL·min-1, and the wavelength was set at 262 nm. The sample was extracted with ethyl acetate.Carbamazepine was used as the internal standard. RESULTS The calibration curves of voriconazole and N-oxidized voriconazole were linear in the range of 0.1-8.0 μg·mL-1, the lower limit of quantitation was 0.1 μg·mL-1, and the intra-assay and inter-assay precision RSDs were between 2% and 10%. The accuracy, method recovery and stability all met the requirements.Twenty-nine patients were monitored with a total of 100 blood samples.The medians (IQRs) of voriconazole concentration, N-oxidized voriconazole concentration, and ratio of N-oxidized voriconazole to voriconazole were 0.87 μg·mL-1 (0.32-1.65 μg·mL-1) and 1.15 μg·mL-1 (0.55-1.67 μg·mL-1) and 1.10(0.66-1.22), respectively. There was a correlation relationship between the concentrations of voriconazole and N-oxidized voriconazole (r=0.603 1, P<0.000 1). CONCLUSION The method is simple, accurate, highly specific, and can simultaneously monitor the concentrations of voriconazole and N-oxidized voriconazole, thus can be used for the pharmacokinetic research of voriconazole and clinical drug monitoring.
罗兴献, 黄琳, 李泰锋, 胡蕾, 刘雪梅, 薛学财, 张海英, 陈月, 冯婉玉. 高效液相二极管阵列检测法测定人血浆中伏立康唑和N-氧化伏立康唑浓度及其对儿童白血病的用药指导[J]. 中国药学杂志, 2019, 54(14): 1169-1175.
LUO Xing-xian, HUANG Lin, LI Tai-feng, HU Lei, LIU Xue-mei, XUE Xue-cai, ZHANG Hai-ying, CHEN Yue, FENG Wan-yu. High Performance Liquid Chromatography Coupling with Photo-diode Array Detector Method for Monitoring Voriconazole and Its Main Metabolite N-oxidized Voriconazole and Its Application to Medication Guidance for Childhood Leukemia. Chinese Pharmaceutical Journal, 2019, 54(14): 1169-1175.
MARKS D I, LIU Q, SLAVIN M. Voriconazole for prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplantation[J] . Expert Rev Anti Infect Ther, 2017, 15(5):493-502.
SCOTT L J, SIMPSON D. Voriconazole: a review of its use in the management of invasive fungal infections[J] . Drugs, 2007, 67(2):269-298.
HOHMANN N, KREUTER R, BLANK A, et al. Autoinhibitory properties of the parent but not of the N-oxide metabolite contribute to infusion rate-dependent voriconazole pharmacokinetics[J] . Br J Clin Pharmacol, 2017, 83(9):1954-1965.
JIN H, WANG T, FALCIONE B A, et al. Trough concentration of voriconazole and its relationship with efficacy and safety: a systematic review and Meta-analysis[J] . J Antimicrob Chemother, 2016, 71(7):1772-1785.
UEDA K, NANNYA Y, KUMANO K, et al. Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders[J] . Int J Hematol, 2009, 89(5):592-599.
WANG T, CHEN S, YOU H, et al. Hepatotoxicity study of voriconazole therapy in patients with invasive fungal infections[J] . Chin Pharm J(中国药学杂志), 2018, 53(4):290-294.
HU L, DAI T T, ZOU L, et al. Therapeutic drug monitoring of voriconazole in children: experience from a tertiary care center in China[J] . Antimicrob Agents Chemother, 2018,62(12):Doi:10.1128/AAC.00955-18.
KARTHAUS M, LEHRNBECHER T, LIPP H P, et al. Therapeutic drug monitoring in the treatment of invasive aspergillosis with voriconazole in cancer patients--an evidence-based approach[J] . Ann Hematol, 2015, 94(4):547-556.
HYLAND R, JONES B C, SMITH D A. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole[J] . Drug Metab Dispos, 2003, 31(5):540-547.
YANNI S B, ANNAERT P P, AUGUSTIJNS P, et al. Role of flavin-containing monooxygenase in oxidative metabolism of voriconazole by human liver microsomes[J] . Drug Metab Dispos, 2008, 36(6):1119-1125.
JEU L, PIACENTI F J, LYAKHOVETSKIY A G, et al. Voriconazole[J] . Clin Ther, 2003, 25(5):1321-1381.
ENCALADA VENTURA M A, SPAN L F, VAN DEN HEUVEL E R, et al. Influence of inflammation on voriconazole metabolism[J] . Antimicrob Agents Chemother, 2015, 59(5):2942-2943.
KUNISADA M, YAMANO N, HOSAKA C, et al. Inflammation due to voriconazole-induced photosensitivity enhanced skin phototumorigenesis in Xpa-knockout mice[J] . Photochem Photobiol, 2018, 94(5):1077-1081.
VERINGA A, TER AVEST M, SPAN L F, et al. Voriconazole metabolism is influenced by severe inflammation: a prospective study[J] . J Antimicrob Chemother, 2017, 72(1):261-267.
YAN M, WU Z F, TANG D, et al. The impact of proton pump inhibitors on the pharmacokinetics of voriconazole in vitro and in vivo[J] . Biomed Pharmacother, 2018, 108:60-64.
NIIOKA T, FUJISHIMA N, ABUMIYA M, et al. Relationship between the CYP2C19 phenotype using the voriconazole-to-voriconazole N-oxide plasma concentration ratio and demographic and clinical characteristics of Japanese patients with different CYP2C19 genotypes[J] . Ther Drug Monit, 2017, 39(5):514-521.
CÉLINE E,OLIVIER M,HÉLÈNE P,et al. Simultaneous Quantification of Voriconazole and Its N-Oxide Metabolite in Human Plasma by an Easy and Rapid Isocratic LC Method with UV Detection [J] . Chromatographia,2008,67(3-4):275-280.
YAMADA T, MINO Y, YAGI T, et al. Rapid simultaneous determination of voriconazole and its N-oxide in human plasma using an isocratic high-performance liquid chromatography method and its clinical application[J] . Clin Biochem, 2012, 45(1-2):134-138.
GOMEZ-LOPEZ A, ALCAZAR-FUOLI L, BERNAL-MARTINEZ L. Simultaneous quantification of systemic azoles and their major metabolites in human serum by HPLC/PDA: role of azole metabolic rate[J] . Diagn Microbiol Infect Dis,2018,92(1):78-83.
THEURETZBACHER U, IHLE F, DERENDORF H. Pharmacokinetic/pharmacodynamic profile of voriconazole[J] . Clin Pharmacokinet, 2006, 45(7):649-663.
LUO X X, HUANG L, LI T F, et al. Simultaneous detection of concentrations of imatinib and voriconazole in human serum by RP-HPLC[J] . Chin J Hosp Pharm(中国医院药学杂志), 2018, 38(1):36-40.
ROFFEY S J, COLE S, COMBY P, et al. UPLC-MS/MS method for the simultaneous determination of imatinib, voriconazole and their metabolites concentrations in rat plasma[J] . J Pharm Biomed Anal,2019,166:6-12.
BARTELINK I H, WOLFS T, JONKER M, et al. Highly variable plasma concentrations of voriconazole in pediatric hematopoietic stem cell transplantation patients[J] . Antimicrob Agents Chemother, 2013, 57(1):235-240.
LIU L, ZHOU X, WU T, et al. Dose optimisation of voriconazole with therapeutic drug monitoring in children: a single-centre experience in China[J] . Int J Antimicrob Agents, 2017, 49(4):483-487.
BRUGGEMANN R J, VAN DER LINDEN J W, VERWEIJ P E, et al. Impact of therapeutic drug monitoring of voriconazole in a pediatric population[J] . Pediatr Infect Dis J, 2011, 30(6):533-534.
EIDEN C, COCIGLIO M, HILLAIRE-BUYS D, et al. Pharmacokinetic variability of voriconazole and N-oxide voriconazole measured as therapeutic drug monitoring[J] . Xenobiotica, 2010, 40(10):701-706.
NARITA A, MURAMATSU H, SAKAGUCHI H, et al. Correlation of CYP2C19 phenotype with voriconazole plasma concentration in children[J] . J Pediatr Hematol Oncol, 2013, 35(5):e219-223.
BARTER Z E, TUCKER G T, ROWLAND-YEO K. Differences in cytochrome p450-mediated pharmacokinetics between chinese and caucasian populations predicted by mechanistic physiologically based pharmacokinetic modelling[J] . Clin Pharmacokinet,2013,52(12):1085-1100.
NAITO T, YAMADA T, MINO Y, et al. Impact of inflammation and concomitant glucocorticoid administration on plasma concentration of triazole antifungals in immunocompromised patients[J] . Clin Chim Acta, 2015, 441:127-132.