目的 定量分析人血浆中加替沙星的浓度,研究加替沙星眼用凝胶连续7 d给药后加替沙星在健康男性受试者体内的暴露特点。方法 建立人血浆中加替沙星的LC-MS-MS定量分析方法,并对该方法的特异性、灵敏度、精密度与准确度、基质效应、回收率、稳定性等进行考察;测定10名男性健康受试者连续7 d滴用加替沙星眼用凝胶后不同时间点血浆样品中加替沙星的浓度。结果 LC-MS/MS定量分析人血浆中加替沙星的线性范围为2~500 ng·mL-1;在5、10、50和400 ng·mL-1浓度水平的准确度(RE)在±15.0%以内,批内精密度(RSD)在1.47%~2.61%之间,批间精密度(RSD)在1.79%~13.1%之间,基质效应、回收率、特异性、稳定性等进行考察均满足要求。受试者连续给药后所有血浆样品中加替沙星的药物浓度均低于定量下限(2 ng·mL-1)。结论 本实验建立了灵敏、准确的加替沙星定量分析方法,受试者连续7 d滴用加替沙星眼用凝胶后在所有血浆样品中加替沙星的药物浓度均低于定量下限(2 ng·mL-1)。
Abstract
OBJECTIVE To determine gatifloxacin in human plasma, and study the exposure characteristics of gatifloxacin in Chinese healthy male volunteers who used Gatifloxacin Eye Gel for 7 d.METHODS LC-MS/MS method was developed for the quantitation of gatifloxacin in human plasma. After protein precipitation with methanol and dilution with water, the chromatographic separation was carried out on an Symmetry C18 column (4.6 mm×100 mm, 5 μm) with a gradient mobile phase consisting of 0.1% formic acid in methanol and 0.1% formic acid in water at a flow rate of 0.5 mL·min-1. The quantitation analysis was performed using multiple reaction monitoring (MRM) at the specific ion transitions of m/z 376.2→261.0 for gatifloxacin and m/z 332.1→288.1 for ciprofloxacin (internal standard) in the positive ion mode with electrospray ionization (ESI) source. Specificity, linearity, precision and accuracy, matrix effects, recovery and stability were investigated to validate the LC-MS/MS method. Plasma samples of different times from 10 Chinese healthy male volunteers were determined, who used Gatifloxacin Eye Gel for 7 d.RESULTS The linear range was 2-500 ng·mL-1. The intra- and inter-day precisions were less than 2.61% and 13.1%, and the accuracy was within±5.0%. Matrix effective, recovery, specificity and stability were within±15.0%. The concentration of gatifloxacin in human plasma was below the lower limit of quantitation (2 ng·mL-1). CONCLUSION This method is sensitive and accuracy for the determination of gatifloxacinin human plasma, and the plasma gatifloxacin level are all below the lower limit of quantitation (2 ng·mL-1) in all subjects.
关键词
加替沙星 /
眼用凝胶 /
LC-MS/MS /
人血浆
{{custom_keyword}} /
Key words
gatifloxacin /
eye gel;LC-MS/MS;human plasma
{{custom_keyword}} /
中图分类号：
R969.2
{{custom_clc.code}}
({{custom_clc.text}})
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] MARTIN P. MPH Clinical Review. Gatifloxacin Clinical BPCA . U. S. Department of Health and Human Services, . http: // www.fda.gov/downloads / drugs / developmentapprovalprocess / developmentresources / ucm187155. pdf
[2] ZHANG Q, CHENG Y L, BAI R W,et al. Pharmacokinetics of gatifloxacin ophthalmic gel in ocular delivery.Chin Pharm J(中国药学杂志), 2007,42(24):1881-1884
[3] SHAH V P, MIDHA K K, FINDLAR J W, et al. Bioanalytical method validation-A revisit with a decade of progress. Pharm Res, 2000, 17(12):1551-1557.
[4] State Food and Drug Administration. The Guidance Principles for Research Methods of Non-Clinical Pharmacokinetics of Chemical Drugs(化学药物非临床药动学研究技术指导原则). 2005.3.
[5] HELMY S A. Simultaneous quantification of linezolid, tinidazole, norfloxacin, moxifloxacin, levofloxacin, and gatifloxacin in human plasma for therapeutic drug monitoring and pharmacokinetic studies in human volunteers.Ther Drug Monit,2013,35(6):770-777.
[6] SOUSA J, ALVES G, CAMPOS G, et al.First liquid chromatography method for the simultaneous determination of levofloxacin, pazufloxacin, gatifloxacin, moxifloxacin and trovafloxacin in human plasma.J Chromatogr B Analyt Technol Biomed Life Sci,2013,930:104-111.
[7] VISHWANATHAN K, MICHAEL G, BARTLETT J T. Determination of gatifloxacin in human plasma by liquid chromatograph/electrospray tandem mass spectrometry.Rapid Commun Mass Sprectrom, 2001,15(12): 915-919.
[8] LIU X, WANG N L, WANG Y L, et al.Determination of drug concentration in queous humor of cataract patients administered gatifloxacin ophthalmic gel. Chin Med J, 2010,123(15): 2105-2110.
[9] SHI Y G, ZHANG J G, YU J C , et al. The clinical pharmacokinetics of gatifloxacin. Chin J Infect Chemother(中国抗感染化疗杂志), 2003,3(5): 264-268.
LOBER, S. ZIEGE, M. RAU, G.et al.Pharmacokineticsof gatifloxacin and interaction with an antacid containing aluminum and magnesium.Antimicrob Agents Chemother,1999,43(5) :1067-1071.
SMYTHE W, MERLE C S, RUSTOMJEE R,et al. Evaluation of initial and steady-state gatifloxacin pharmacokinetics and dose in pulmonary tuberculosis patients by using monte carlo simulations. Antimicrob Agents Chemother, 2013,57(9):4164-4171.
LUBASCH A, KELLER I, BORNER K,et al.Comparative pharmacokinetics ofciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, trovafloxacin, and moxifloxacin after single oral administration in healthy volunteers.Antimicrob Agents Chemother, 2000,44 (10):2600-2603.
NIKI Y, YOSHIDA K, MIYASHITA N,et al. Evaluation of clinical dosage of gatifloxacin for respiratory tract infections in elderly patients based on pharmacokinetics/pharmacodynamics (PK/PD) . J Infect Chemother,2008,14(4):296-304.
SRINIVAS N, NARASU L, SHANKAR B P. Development and validation of a HPLC method for simultaneous quantitation of gatifloxacin, sparfloxacin and moxifloxacin using levofloxacin as internal standard in human plasma: Application to a clinical pharmacokinetic study. Biomed Chromatogr, 2008,22(11):1288-1295.
ZONG G,LI Q,JI J M.et al.Analysis of 278 cases of adverse reaction caused by gatifloxacin. Chin Pharm J(中国药学杂志),2008,43(8):636-637.
LIU H Y,BU Y L. Summary of hypoglycemia literature caused bygatifloxacin.Chin J Drug Abuse Prev Treat(中国药物滥用防治杂志),2014,20(3): 177-186.
TIAN H, GUO D H, CHEN C,et al. Clinical analysis of cases with dysglycemia associated with gatifloxacin.Advier Drug Redict J(药物不良反应杂志),2006,8 (5):339-342.
ZHOU B, ZHANG J,PEI Z E, et al. A follow-up study of effects of gatifloxacin on blood glucose in inpatients. Advier Drug Redict J(药物不良反应杂志), 2008,10(4):229-233.
ZVONAR R. Gatifloxacin-induced dysglycemia. Am J Health Syst Pharm,2006,63(21):2087-2092.
ALI T, GREENFIELD R A, SCOFIELD H, et al.Gatifloxacin-associated hypoglycemia.J Okla State Med Assoc,2007 ,100(11):425-428.
ONYENWENYI A J, WINTERSTEIN A G, HATTON R C. An evaluation of the effects of gatifloxacin on glucose homeostasis. Pharm World Sci,2008,30(5):544-549.
PARK-WYLLIE L Y, JUURLINK D N, KOPP A,et al. Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med,2006, 354(13):1352-1361.
MOHR J F, MCKINNON P S, PEYMANN P J.et al.A retrospective, comparative evaluation of dysglycemias in hospitalized patients receiving gatifloxacin, levofloxacin, ciprofloxacin, or ceftriaxone. Pharmacotherapy,2005,25(10):1303-1309.
Gatifloxacin. FDA Informationfor Healthcare Professionals. http:// www. fda. gov/downloads / drugs / drugsafety / postmarketdrugsafetyinformationforpatientsandproviders / ucm126166. pdf.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
PDF(1115 KB)
