Effects of the pharmacokinetic interaction between orally administered sirolimus and cyclosporine on the synergistic prolongation of heart allograft survival in rats.
Effects of the pharmacokinetic interaction between orally administered sirolimus and cyclosporine on the synergistic prolongation of heart allograft survival in rats.
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口服西罗莫司和环孢素之间的药代动力学相互作用对协同延长大鼠同种异体心脏移植存活的影响。
DOI：
10.1097/00007890-199610150-00018
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发表时间：
1996
期刊：
影响因子：
6.2
通讯作者：
Kahan,BD
中科院分区：
文献类型：
--
作者：
Stepkowski,SM;Napoli,KL;Wang,ME;Qu,X;Chou,TC;Kahan,BD
西罗莫司（SRL）与环孢素（CsA）联合口服（而非连续静脉输注）会产生药代动力学相互作用，即SRL （[SRL WB]）和CsA （[CsA WB]）的全血谷浓度升高。在Buffalo （RT1 b）同种异体心脏移植的Wistar Furth （RT1 u）受体中，研究了这种药代动力学相互作用对SRL和CsA之间协同作用的影响。口服SRL 14天的疗程产生剂量依赖性延长同种异体心脏移植的时间：在未治疗的对照组中，每天0.5 mg/kg SRL使平均生存时间（MST）从6.4±0.5天延长至12.3±3.8天（P< 0.05）；SRL 1.0 mg/kg / d使MST延长至18.0±5.5 d (P< 0.01)；2.0 mg/kg SRL / d组MST延长至52.5±13.2 d (P< 0.01)；4.0 mg/kg SRL / d使MST延长至90.0±41.1 d （P< 0.01）。口服与连续静脉注射SRL的体内效应比较表明，SRL的口服生物利用度小于10%。口服SRL和CsA联合使用可协同延长同种异体心脏移植存活，联合指数为0.01-0.64（联合指数< 1表明协同相互作用）。在双药联合治疗的大鼠中，CsA使SRL的生物利用度提高了2 - 11倍，SRL使CsA的生物利用度提高了2 - 3倍，从而显著降低了每种药物的口服有效剂量（ED）值。仅SRL的ed50为每天2.4 mg/kg，其平均[SRL WB]为13.2 ng/ml。仅CsA的ed50为每天8.0 mg/kg，平均[CsA WB]为1642 ng/ml。然而，当两种药物联合使用时，ed50效应仅为每天0.34 mg/kg SRL （[SRL WB]= 1.1 ng/ml）和2.1 mg/kg CsA （[CsA WB]= 326 ng/ml）。单独来说，每天0.34 mg/kg的SRL产生ED 9，平均[SRL WB]为0.6 ng/ml，每天2.1 mg/kg的CsA产生ED 22，平均[CsA WB]为174 ng/ml。因此，口服SRL和CsA之间的药代动力学相互作用有助于两种药物在体内的协同作用。
Oral administration, but not continuous intravenous infusion, of sirolimus (SRL) in combination with cyclosporine (CsA) produces a pharmacokinetic interaction, namely increases in the whole blood trough concentrations of SRL ([SRL WB]) and CsA ([CsA WB]). The effects of this pharmacokinetic interaction on the synergism between SRL and CsA was examined in Wistar Furth (RT1 u) recipients of Buffalo (RT1 b) heart allografts. A 14-day course of oral SRL produced dose-dependent prolongation of heart allografts: in untreated controls, 0.5 mg/kg SRL per day extended the mean survival time (MST) from 6.4±0.5 days to 12.3±3.8 days (P< 0.05); SRL at 1.0 mg/kg per day prolonged the MST to 18.0±5.5 days (P< 0.01); at 2.0 mg/kg SRL per day, MST was extended to 52.5±13.2 days (P< 0.01); and 4.0 mg/kg SRL per day prolonged MST to 90.0±41.1 days (P< 0.01). Comparison of the in vivo effects after oral versus continuous intravenous SRL administration suggested that the oral bioavailability of SRL is less than 10%. Combinations of oral SRL and CsA synergistically prolonged heart allograft survival, as documented by combination index values of 0.01-0.64 (combination index< 1 indicates synergistic interaction). In rats treated with dual drug combinations, CsA increased the bioavailability of SRL by two-to elevenfold, and SRL increased the bioavailability of CsA by two-to threefold, thereby significantly decreasing the oral effective dose (ED) values for each drug. The ED 50 for SRL alone is 2.4 mg/kg per day, which produces an average [SRL WB] of 13.2 ng/ml. The ED 50 for CsA alone is 8.0 mg/kg per day, which produces an average [CsA WB] of 1642 ng/ml. However, when the two drugs are combined, the ED 50 effect is achieved with only 0.34 mg/kg SRL per day ([SRL WB]= 1.1 ng/ml) and 2.1 mg/kg CsA per day ([CsA WB]= 326 ng/ml). Individually, 0.34 mg/kg SRL per day produces an ED 9 with an average [SRL WB] of 0.6 ng/ml, and 2.1 mg/kg CsA per day produces an ED 22 with an average [CsA WB] of 174 ng/ml. Thus, the pharmacokinetic interaction between oral SRL and CsA contributes to the in vivo synergism between the two drugs.
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地红霉素对健康受试者和肾移植患者中环孢素药代动力学的影响。
影响因子：
4.2
作者：
K. Bachmann;T. Sullivan;J. Reese;L. Jauregui;K. Miller;M. Scott;G. Sides;R. Shapiro
通讯作者：
R. Shapiro
影响因子：
2.8
作者：
DIAS, VC;YATSCOFF, RW
通讯作者：
YATSCOFF, RW
雷帕霉素，一种强效免疫抑制药物，用于大鼠血管化心脏、肾脏和小肠移植。
影响因子：
6.2
作者：
Stepkowski,SM;Chen,H;Daloze,P;Kahan,BD
通讯作者：
Kahan,BD
兔异位心脏移植模型中雷帕霉素和环孢素血药浓度与抑制同种异体移植排斥反应的关系1
影响因子：
6.2
作者：
J. Fryer;R. Yatscoff;E. Pascoe;J. Thliveris
通讯作者：
J. Thliveris
影响因子：
6.2
作者：
KAHAN, BD;GIBBONS, S;CHOU, TC
通讯作者：
CHOU, TC