芬太尼口颊片在比格犬体内的药动学研究  

Study on Pharmacokinetics of Fentanyl Buccal Tablet in Beagle Dogs

作　　者：何京亚 桑广泽 乔友备 贺欣 余喆 吴红 HE Jingya;SANG Guangze;QIAO Youbei;HE Xin;YU Zhe;WU Hong(Teaching and Research Section of Pharmaceutical Chemistry and Pharmaceutical Analysis, Dept. of Pharmacy, Air Force Military Medical University,Xi’an 710032,China)

机构地区：[1]空军军医大学药学系药物化学与药物分析学教研室

出　　处：《中国药房》2019年第15期2052-2055,共4页China Pharmacy

基　　金：国家科技重大新药创制项目(No.2014ZX09J14107-04B)

摘　　要：目的:建立比格犬体内枸橼酸芬太尼血药浓度的测定方法,并进行芬太尼口颊片的药动学研究。方法:取6只比格犬给予芬太尼口颊片1片(675μg/片,含服),分别于给药后2、5、10、15、30、45、60、90、120、240、360、480、720 min取静脉血1 mL,经甲醇沉淀后,采用液相色谱-串联质谱(LC-MS/MS)法[色谱条件:色谱柱为Agilent C18,流动相为甲醇-0.02%甲酸水溶液(95:5,v/v),流速为0.5 mL/min,进样量为5μL,柱温为30℃;质谱条件:采用电喷雾电离源,正离子多反应监测,检测离子为枸橼酸芬太尼质荷比(m/z)337.1→1 88.0、卡马西平(内标)m/z 237.1→194.1],测定枸橼酸芬太尼的血药浓度,并采用DAS 2.0软件计算药动学参数。结果:枸橼酸芬太尼检测质量浓度的线性范围为1.0~325.0 ng/mL(r=0.998),精密度试验的日内RSD<5%(n=6),日间RSD<6%(n=3);平均回收率为(94.65±6.32)%^(99.21±3.24)%(n=6);基质效应的RSD<15%(n=6),稳定性试验的RE在±6.2%内(n=3)。芬太尼口颊片在比格犬体内的药动学参数tmax为(32.5±6.1)min,t1/2为(211.8±47.4)min,cmax为(40.3±1.9)ng/mL,CLz/F为(0.006±0.001)L/(min·kg),AUC0-720min为(7 564.0±1 576.7)ng·min/mL(n=6)。结论:本方法简便、可行、准确。芬太尼口颊片在比格犬体内具有良好的速释、缓释双相释药特性。OBJECTIVE:To establish a method for blood concentration determination of Fentanyl buccal tablet in Beagle dogs,and to study its pharmacokinetics.METHODS:A total of 6 Beagle dogs were given Fentanyl buccal tablet 1 tablet(675 μg/tablet,buccally).The blood samples were collected 2,5,10,15,30,45,60,90,120,2/40,360,480,720 min after administration.After precipitated by methanol,LC-MS/MS method[the determination was performed on Agilent Ci. column with mobile phase consisted of methanol-0.02% formic acid aqueous solution(95:5,V/V)at the flow rate of 0.5 mL/min.The sample size was 5 μL and the column temperature was 30 ℃.Mass spectrometric conditions:electrospray ionization source in the multiple reaction monitoring mode was used to detect ions,fentanyl citrate:m/z 337.1→188.0;carbamazepine(internal standand):m/z 237.1→194.1]was used to determine the blood concentration of fentanyl citrate;the pharmacokinetic parameters were calculated by using DAS 2.0 software.RESULTS:The linear range of fentanyl citrate were 1.0-325.0 ng/mL(r=0.998);inter-day RSDs of precision test were lower than 5%(n=6),and intra-day RSDs were lower than 6%(n=3);average recoveries were(94.65 ±6.32)%-(99.21 ±3.24)%(n=6).RSDs of matrix effect was lower than 15%(n=6);RE of stability tests were within ±6.2%(n=3).The pharmacokinetic parameters of Fentanyl buccal tablet in Beagle dogs included that tmax was(32.5±6.1)min;t1/2 was(211.8±±47.4)min;cmax was(40.3±1.9)ng/mL;CLz/F was(0.006±0.001)L/min·kg);AUC0-720 min was(7 564.0±1 576.7)ng·min/mL(n=6).CONCLUSIONS:The method is simple,feasible and accurate.Fentanyl buccal tablet have good fast-release and slow-release biphasic release characteristics in Beagle dogs.

关 键 词：芬太尼 口颊片 液相色谱-串联质谱法 比格犬 血药浓度 药动学 

分 类 号：R969.1[医药卫生—药理学]