金霉素微囊颗粒在猪体内的比较药动学研究

【目的】采用高效液相色谱-串联质谱法(HPLC-MS/MS)建立了金霉素在猪血浆中的药动学检测方法,以三元健康杂交猪为对象,研究了10%和15%金霉素微囊颗粒在猪体内的药物代谢动力学,为金霉素的临床应用提供依据。【方法】16头大长白三元杂交猪,体重(20±2.5)kg,随机分为禁食组和非禁食组2组,采用三药剂三周期三交叉试验设计,分别按10 mg·kg^-1 b.w.静注盐酸金霉素溶液、40 mg·kg^-1 b.w.灌服10%和15%金霉素微囊颗粒。每次给药间隔为7 d,根据试验前设定好的时间点采集血样,分离血浆,进行HPLC-MS/MS测定,血药浓度-时间数据采用WinNonlin5.2.1软件非房室模型处理,计算主要药动学参数。血浆样品用0.1 mol·L^-1Na2EDTA-McIlvaine缓冲液超声提取,HLB固相萃取柱净化,35℃水浴吹干后用甲醇定容,进行HPLC-MS/MS分析测定。色谱柱为CNW C18柱;流动相为乙腈-0.1%甲酸,梯度洗脱,流速为0.25 mL·min-1;电喷雾离子源,多级反应监测正离子...

Pharmacokinetics of Chlortetracycline Microspheres in Pigs

【Objective】A method was developed for the determination of chlortetracycline in swine plasma with high- performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The pharmacokinetics of chlortetracycline in pigs, including chlortetracycline hydrochloride, 10% chlortetracycline microspheres and 15% chlortetracycline microspheres were studied.【Method】Pharmacokinetics of chlortetracycline were investigated after intravenous and oral administration to pigs. Sixteen cross-bred pigs(Duroc×Landrace×Yorkshire) weighing (20±2.5) kg received a dose of 10 mg·kg^-1 of chlortetracycline hydrochloride intravenously and 40 mg·kg^-1 of 10% chlortetracycline microspheres and 15% chlortetracycline microspheres orally in both the fasted and the feeding condition in a three-way crossover design with one week washout period between each administration. Blood samples were collected in different time set before the experiment. The swine plasma samples were ultrasonic extracted with 0.1 mol·L^-1 Na₂EDTA-McIlvaine buffer. Then the extract was loaded on the HLB solid phase extraction (SPE) cartridge. After evaporation by nitrogen with water bath at 35℃, the extract was redissolved with methanol. Chlortetracycline was separated using a CNW C18 column with a mobile phase of acetonitrile -0.1% formic acid. The mobile phase was gradient elution at the flow rate of 0.25 mL·min^-1. Chlortetracycline was analyzed by mass spectrometry equipped with electrospray ionization in the multiple reaction monitoring and positive ion mode and determined by an external standard quantitation. In the range of 5-500 ng·mL^-1, the calibration curves of chlortetracycline from swine plasma showed good linearity (r>0.9990). The limit of detection (LOD) was 5 ng·mL^-1 and the limit of quantification (LOQ) was 10 ng·mL^-1. The average recovery of chlortetracycline was 76.90%-89.25% at low, medium and high concentration while the inter-day and intra-day coefficient of variations were 2.97%-9.45% and 6.16%-13.39%, respectively. The method was accurate, sensitive and suitable for the determination of chlortetracycline in swine plasma.【Result】Chlortetracycline concentration-time data fitted to a non-compartment model were analyzed by WinNonlin5.2.1 pharmacokinetic program after intravenous and oral administration in both fasted and fed pigs. The main pharmacokinetic parameters for chlortetracycline hydrochloride in fasted pigs and feeding pigs were follows: AUC_0-∞ (57.42±23.53) mg·h·mL^-1, (37.58±21.30) mg·h·mL^-1; V/F (5.67±2.12) L·kg^-1, (12.59±6.43) L·kg^-1; MRT(13.87±2.00) h, (22.17±14.47) h; t_1/2(19.93±5.26 ) h, (27.79±12.82) h, respectively. After receiving 10% chlortetracycline microspheres and 15% chlortetracycline microspheres without feeding, the parameters were as follows: AUC_0-∞ (34.46±10.28) mg·h·mL^-1, (33.15±12.76) mg·h·mL^-1; C_max (2.48±1.05) mg·mL^-1, (2.97±1.88) mg·mL^-1, T_max (4.88±1.25) h, (3.13±1.55) h; V/F (31.53±15.98) L·kg^-1, (32.30±9.69) L·kg^-1; MRT (19.93±3.83) h, (17.41±1.80) h; t_1/2(16.87±3.49) h, (17.13±3.58) h; F(17.03±0.08) %, (15.82±5.16) %, respectively. In feeding group, after receiving 10% chlortetracycline microspheres and 15% chlortetracycline microspheres, the parameters were as follows: AUC_0-∞ (20.81±7.46) mg·h·mL^-1, (19.72±5.69) mg·h·mL^-1; C_max (1.02±0.38) mg·mL^-1, (0.95±0.32) mg·mL^-1; T_max (6.38±4.44) h, (8.00±5.24) h; V/F (52.40±22.90) L·kg^-1,(52.47±19.69) L·kg^-1; MRT (24.67±9.52) h, (23.37±4.21) h; t_1/2 (18.57±10.67) h, (16.64±5.12) h; F (16.07±6.78)%, (15.26±5.26)%, respectively. 【Conclusion】The results of studies showed that chlortetracycline was absorbed slowly, distributed widely and had slow elimination and low bioavailability in pigs after receiving chlortetracycline microspheres orally. Compared with the fasting group, 10% and 15% chlortetracycline microspheres in the feeding group reached a slower peak time and a lower peak concentration, while the apparent distribution volume was larger and the bioavailability was lower, but the difference was not significant. This result indicated the feed did not affect the absorption of chlortetracycline in the gastrointestinal tract of pigs, but changed the pharmacokinetic process of chlortetracycline entering the body.