PHARMACOKINETICS OF ORALLY AND INTRAVENOUSLY ADMINISTERED CYCLOSPORINE IN PRE-KIDNEY TRANSPLANT PATIENTS
PHARMACOKINETICS OF ORALLY AND INTRAVENOUSLY ADMINISTERED CYCLOSPORINE IN PRE-KIDNEY TRANSPLANT PATIENTS
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DOI：
10.1002/j.1552-4604.1994.tb03967.x
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发表时间：
1994-01-01
影响因子：
2.9
通讯作者：
BENET, LZ
中科院分区：
文献类型：
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作者：
AWEEKA, FT;TOMLANOVICH, SJ;BENET, LZ
对8例肾移植患者进行了环孢素(CsA)和4种代谢物的药代动力学研究，以比较移植后患者和正常志愿者的代谢模式。每个受试者接受一次4毫克/公斤的静脉注射和一次10毫克/公斤的口服剂量，间隔一周的洗脱期。分别于服药前及服药后0.5、1、1.5、2、2.5、3、4、6、8、10、12、14、24小时采集血样。用高压液相色谱法测定环孢素血、血浆和代谢产物(M17、M1、M18、M21)的浓度。CsA静脉给药后的平均(+/-)标准差为.47±.15 L/小时/公斤，稳态分布体积(V-ss)为1.9±.5 L/公斤，平均停留时间为4.4+/-1.8小时。血浆平均清除率为0.70±0.31 L/小时/公斤，V-SS为2.4±-1.2 L/公斤，MRT为3.7±-2.2小时。环孢素在血液和血浆中的生物利用度分别为24+/-11和24+/-15%。在健康志愿者中，Clear和V-ss的值大约比可比估计值高出30%到100%，但F和MRT没有改变到这个程度。这些变化可能是尿毒症患者蛋白结合力降低的基础。与静脉给药相比，口服给药后M17和M1与CsA的曲线下面积比分别平均增加1.7倍和3.9倍，表明在首过代谢过程中转化率增加。
The pharmacokinetics of cyclosporine (CSA) and four metabolites were evaluated in eight hemodialysis subjects awaiting renal transplantation to compare metabolic patterns with those observed in post-transplant patients and normal volunteers. Each subject received a single 4-mg/kg intravenous and a single 10-mg/kg oral dose separated by a 1-week washout period. Blood samples were collected before and at .5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, and 24 hours after CSA dosing. Cyclosporine blood, plasma, and metabolite (M17, M1, M18, M21) levels were determined by high-pressure liquid chromatography. Mean (+/- standard deviation) CSA blood clearance was .47 +/- .15 L/hour/kg, steady-state volume of distribution (V-ss) was 1.9 +/- .5 L/kg, and mean residence time (MRT) was 4.4 +/- 1.8 hours after intravenous dosing. With plasma, mean clearance was .70 +/- .31 L/hour/kg, V-ss was 2.4 +/- 1.2 L/kg, and MRT was 3.7 +/- 2.2 hours. Cyclosporine bioavailability (F) averaged 24 +/- 11 and 24 +/- 15%, using blood and plasma, respectively. Values for clearance and V-ss were approximately 30 to 100% greater than comparable estimates in healthy volunteers, but F and MRT were not altered to this extent. These changes might be explained on the basis of decreased protein binding in uremic patients. The area under the curve ratio for M17 and M1 to CSA increased an average of 1.7- and 3.9-fold, respectively, after oral dosing compared with intravenous administration, indicating increased conversion during first-pass metabolism.