福建医科大学附属协和医院
研究生：王非
导师：黄显副教授
中文摘要
目的摸索同时测定大鼠全血中环孢素(CsA) 、伊曲康唑(ICZ)浓度的方法，研究大鼠体内CsA微乳化剂与ICZ口服液的药动学性质及两者合用对其药动学的相互影响。 方法30只雄性SD大鼠随机均分成A、B、C三组。d1, A、B组大鼠分别单次灌服CsA（10mg·kg-1）（A1）和ICZ（10mg·kg-1）（B1），C组大鼠单次合用CsA（10mg·kg-1）和ICZ（10mg·kg-1），三组大鼠均于灌胃结束0，1，2，3，4，6，8，12，24，36，48，72h尾部取血0.3～0.35mL。洗脱一个月。第二阶段，A、B组每日分别灌服两次CsA （10mg·kg-1）（A2）和ICZ（10mg·kg-1）（B2），连续7天，并于每日早晨灌胃结束2h采血，另A2组灌胃前亦取血一次；d8上午，A、B组大鼠同时合用CsA（10mg·kg-1）和ICZ（10mg·kg-1）并按d1取血点取血。所有血样经预处理后用HPLC法测定：C18柱(150mm×4.6mm,5 µm)；流动相：乙腈-水(76:24,V/V)；流速:1.0mL·min-1；检测波长：210nm；柱温：三相马达
无动力除尘
68 o C。测定结果采用DAS软件拟合，求算药动学参数，并用SPSS软件对各组参数进行统计学分析。结果A1组单剂量灌服CsA，一小时迅速达峰浓度，t1/2β=11.26±1.43(h)。而单剂量合用ICZ的C组与预先服用ICZ一周达稳态后再单剂量灌服CsA的B2组， CsA的平均AUC 0-∞从（11.0±2.8）µg·h·mL-1分别上升到和（16.2±8.8）µg·h·mL-1和（21.5±5.7）µg·h·mL-1，上升47%和95%（P<0.01）；B2组CsA的峰浓度从（1.76±0.29）µg·ml-1上升到（2.18±0.25）µg·h·mL-1，上升23.9%（P<0.05）。 B1组单剂量灌服ICZ，T max=3.43±0.52 (h)，t1/2β= 20.6±7.47 (h)，而单剂量合用CsA 的C组与预先服用CsA一周达稳态后再单剂量灌服CsA的A2组，ICZ的平均AUC 0-∞
从（4.2±2.9）µg·h·mL-1分别上升到（5.5±4.5）µg·h·mL-1（P<0.05）和（6.7±3.8）µg·h·mL-1（P<0.01），分别上升61%和31%；A2组峰浓度从（0.70±0.31）µg·mL-1上升到（0.94±0.43）µg·h·mL-1，上升34%（P<0.05）。
结论在大鼠体内，CsA与ICZ合用对彼此的多项药动学参数均有显著影响。当一种药物多次给药达稳态浓度时，一旦合用另一种药物，两者的消除半衰期都将明显延长，峰浓度大幅增加，生物利用度显著提高。即使单剂量同时合用，两者生物利用度亦会显著提高。提示临床合用两种药物时，应适当降低给药剂量。严密监测血药浓度并随时调整剂量，保障病人用药安全，确保临床移植手术的成功。
喷香器
【关键词】环孢素伊曲康唑HPLC 药动学细胞素P450 3A4
Pharmacokinetic Evaluation of the Drug Interaction between
Cyclosporine and Itraconazole in Rats
锅炉减温减压装置
Union Hospital, Fujian Medical University
Postgraduate: Wang Fei
变速箱线束Supervisor: Prof. Huang Xian
Abstract
检查井盖
Objective: Aim to establish an analytical method in whole blood sample for both Cyclosporine (CsA) and Itraconazole (ICZ)by high-performance liquid chromatograph (HPLC).To evaluate the pharmacokinetics and the interaction between CsA microemulsion and ICZ oral solution in rats.
Methods:Thirty male Sprague-Dawley rats were equally divided into three groups (A,B, and C) by random design according to weight. In the first stage , the rats in group A and B were intragastrically
administered CsA (10 mg·kg-1 )（A1）and ICZ(10mg·kg-1 )（B1）separately , the rats in group C co-administered single-dose CsA and ICZ(10 mg·kg-1 ),then blood samples (0.3～0.35mL) were collected from the tail at 0, 1, 2, 3, 4, 6, 8, 12, 24, 36,48 and72 h. In the second stage, CsA and ICZ(10 mg·kg-1 )was separately treated to the rats in group A (A2)and B(B2) twice a day for 7days,the blood sample was collected at the 2th hour after every morning’s intragastration and there was a extra sample collection for group A before every morning’s intragastration .Day 8 ,both groups orally co-administered CsA and ICZ(10 mg·kg-1 ). Blood samples were collected according to the schedule of the first stage. The whole blood concentration of CsA and ICZ was pretreated and determined by HPLC. Conditions:Shim—Pack C18((150mm×4.6mm,5 µm))as analytical column, the mobile phase consisting of Acetonitrile : Water(76:24, V/V)at the flow rate of 1.0mL/min.TheUV detector was set at 210nm and the column was controlled at 68o C．Main pharmacokinetic parameters were calculated by DAS and compared by SPSS.
Results: In group A 1，single oral dosing of CsA, T max=1(h), t1/2β=20.6±7.47 (h).As to group C (co-administrated immediately)and B2 (combined single dose of CsA with ICZ when ICZ approached the steady-state blood concentration),the AUC 0-∞of CsA were increased from （ 11.0±2.8）µg·h·m L-1 to（ 16.2±8.8）and（ 21.5±5.7）µg·h·m L-1 separately,increased by 47% and 95% (P <0.01).
Compared with group A 1,the C max of CsA in group B2 increased from （1.76±0.29）µg·m L-1 up to（2.18±0.25）µg·m L-1 , increased by 23.9%, (P<0.05）.
In group B 1，single oral dosing of ICZ, T max=1(h), t1/2β=11.26±1.43(h).As to group C (co-administrated immediately)and A2(combined single dose of ICZ with CsA when CsA approached the steady-state concentration),the AUC 0-∞of ICZ were increased from（4.2±2.9）µg·h·m L-1 to（ 5.5±4.5）µg·h·m L-1，（P<0.05）and（ 6.7±3.8）µg·h·m L-1（P<0.01）separately, increased by 31% and 61%. Compared with group B 1, the mean C max of group A2 increased from（0.70±0.31）µg·m L-1 to（0.94±0.43）µg·m L-1 , increased by 34% (P<0.05).
Conclusion: In rats, the co-administration of CsA and ICZ had significant mutual effects on many pharmacokinetic parameters. When one comes to the steady state concentration after multiple dose, the elimination half life of both drugs would significantly prolonged once co-administrated with the other one. Meanwhile the C max and bioavailability would be remarkable improved. The bioavailability would also be increased when co-administrated at the first dose.It was indicated that the clinical dosage should be reduced when they were used together. There should be close therapeutic drug monitoring and dosage adjustment is necessary according to the monitoring results,in order to assure medication safety and promote their transplantation success rate.
Key words : Cyclosporine; Itraconazole; HPLC; Pharmacokinetic; CYP3A4
英文缩略词表
英文缩写英文全称中文名称CsA Cyclosporine
A 环孢素
ICZ Itraconazole 伊曲康唑SPSS Statistical Package for Social Science 社会科学统计套装软件P-gp Permeability
glycoprotein P-糖蛋白
SD Sprague-
Dawley
斯泼累格•多雷（远交大鼠）
DAS Drug And Statistics for Windows 药动学参数处理软件HPLC High Performance Liquid Chromatography 高效液相谱AUC Area under the curve 曲线下面积
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