CYCLOSPORIN - PHARMACOKINETICS AND DETAILED STUDIES OF PLASMA AND ERYTHROCYTE BINDING DURING INTRAVENOUS AND ORAL-ADMINISTRATION
CYCLOSPORIN - PHARMACOKINETICS AND DETAILED STUDIES OF PLASMA AND ERYTHROCYTE BINDING DURING INTRAVENOUS AND ORAL-ADMINISTRATION
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DOI：
10.1007/bf01046701
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发表时间：
1988-01-01
影响因子：
2.9
通讯作者：
SOLOMON, LR
中科院分区：
文献类型：
--
作者：
LEGG, B;GUPTA, SK;SOLOMON, LR
基于未结合浓度比总血浆或血液浓度更好地与反应相关，在肾移植患者中研究了环孢菌素在血液内和血浆组分中分布的受试者间和受试者内变异性。还研究了药代动力学方面。分析来自通过72小时静脉内输注和口服（7 mg. kg-1，每日两次）。在开始静脉输注后18小时内达到稳态;血浆数据最佳拟合为双指数方程，半衰期为0.13-1.02 h和4.3-13.9 h，与两个阶段相关。平均血浆清除率为700 ml/min。通过RIA和HPLC测定的输注期间浓度相当。口服曲线显示快速和广泛的流产。血浆峰浓度为1460-1880 μ g cntdot。1-1在给药后2-4小时发生，生物利用度估计值为41- 113%。RIA测定的浓度高于HPLC。在37 ℃下测量环孢菌素的血液与血浆浓度比C随着血浆浓度的增加而降低，随着红细胞压积的增加而增加。通过超离心法测量的未结合分数范围为0.042-0.122，平均值为0.068，在一些患者中变化很小，但在其他患者中随时间发生系统性变化。发现环孢菌素结合不仅与甘油三酯有关，而且更特别地与血浆中的胆固醇相关脂蛋白有关。监测胆固醇可能有助于识别结合极端或结合差异很大的患者。
On the basis that unbound concentration better correlates with responses than total plasma or blood concentration, the inter- and intra-subject variability in the distribution of cyclosporin within blood and to plasma components was studied in renal transplant patients. Pharmacokinetic aspects were also studied. Blood samples were analysed from patients who received the drug both by a 72-h i.v. infusion and orally (7 mg .cntdot. kg-1 twice daily). Steady-state was reached within 18 h of starting the i.v. infusion; the plasma data were best fitted by a biexponential equation with half-times of 0.13-1.02 h and 4.3-13.9 h, associated with the two phases. The mean plasma clearance was 700 ml/min. Concentrations during the infusions measured by RIA and HPLC were comparable. Oral profiles showed rapid and extensive aborption. The peak plasma concentrations were 1460-1880 .mu.g .cntdot. 1-1 and occurred 2-4 h after dosing, with bioavailability estimates of 41-113%. Concentrations measured by RIA were higher than by HPLC. Blood-to-plasma concentration ratio measurements of cyclosporin at 37.degree. C decreased with increasing plasma concentration and increased with haematocrit. Fraction unbound, measured by ultracentrifugation, was the range 0.042-0.122 with an averaged of 0.068, and varied little in some patients but showed systematic changes with time in others. Cyclosporin binding was found to be related not only to the triglyceride but, more particularly, to the cholesterol-related liporproteins in plasma. Monitoring cholesterol may be helpful in identifying patients with extremes in binding or with widely varying binding.