Pharmacokinetic Interactions between Sirolimus and Microemulsion Cyclosporine When Orally Administered Jointly and 4 Hours Apart in Healthy Volunteers
Pharmacokinetic Interactions between Sirolimus and Microemulsion Cyclosporine When Orally Administered Jointly and 4 Hours Apart in Healthy Volunteers
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健康志愿者联合口服并间隔 4 小时服用西罗莫司和微乳环孢素的药代动力学相互作用
DOI：
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发表时间：
2003
影响因子：
2.9
通讯作者：
W. Jusko
中科院分区：
文献类型：
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作者：
J. Zimmerman;D. Harper;Jay Getsy;W. Jusko
西罗莫司（RAPA）和环孢素（CsA）是在肾移植患者中同时使用的免疫抑制化合物。两种药物均为口服给药，具有共同的肠和肝代谢以及肠转运机制，因此可能存在药代动力学药物相互作用。在15名男性和6名女性志愿者中完成了一项单次给药、开放标签、4阶段、4种治疗、随机交叉研究。每例受试者接受10 mg RAPA单药口服给药（Rapamune口服溶液）、300 mg CsA单药口服给药（3 × 100 mg Neoral软明胶胶囊）、RAPA和CsA联合给药以及CsA后延迟4小时接受RAPA给药。采集血样144小时（RAPA）或48小时（CsA），并通过液相色谱/串联质谱法（RAPA）或放射免疫测定法（CsA）进行分析。当联合给药时，CsA显著增加RAPA的生物利用度，Cmax、tmax和AUC分别增加116%、92%和230%。然而，当在CsA后4小时给予RAPA时，RAPA Cmax、tmax和AUC分别仅增加37%、58%和80%。CsA不影响t1/2或平均滞留时间（MRT）的任何模式的联合给药。RAPA没有显着影响联合或延迟联合给药后CsA的生物利用度。可以得出结论，CsA显著增加RAPA的生物利用度，这可能归因于大肠和肝脏首过效应，而不是消除改变。RAPA不影响CsA的生物利用度。
Sirolimus (RAPA) and cyclosporine (CsA) are immunosuppressive compounds that are being used concomitantly in renal transplant patients. Both drugs are dosed orally, have common intestinal and hepatic metabolism and intestinal transport mechanisms, and thus offer potential for pharmacokinetic drug interactions. A single‐dose, open‐label, four‐period, four‐treatment, randomized crossover study was completed in 15 male and 6 female volunteers. Each subject received a 10‐mg oral dose of RAPA alone (Rapamune Oral Solution), a 300‐mg oral dose of CsA alone (3 × 100‐mg Neoral Soft Gelatin Capsules), RAPA and CsA jointly, and CsA followed by RAPA delayed by 4 hours. Blood samples were collected for either 144 hours (RAPA) or 48 hours (CsA) and analyzed by either liquid chromatography/tandem mass spectrometry (RAPA) or radioimmunoassay (CsA). RAPA bioavailability was markedly increased by CsA when given jointly, with Cmax, tmax, and AUC being increased 116%, 92%, and 230%, respectively. However, when RAPA was administered 4 hours after CsA, increases in RAPA Cmax, tmax, and AUC were only 37%, 58%, and 80%, respectively. CsA did not affect t1/2 or mean residence time (MRT) by either mode of combined administration. RAPA did not significantly affect CsA bioavailability after either joint or delayed combined administrations. It was concluded that CsA markedly increases the bioavailability of RAPA, which may be attributed to a large intestinal and hepatic first‐pass effect, rather than altered elimination. RAPA did not affect the bioavailability of CsA.
影响因子：
6.2
作者：
KAHAN, BD;GIBBONS, S;CHOU, TC
通讯作者：
CHOU, TC