An in vitro method for predicting in vivo oral bioavailability of novel immunosuppressive drugs
An in vitro method for predicting in vivo oral bioavailability of novel immunosuppressive drugs
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DOI：
10.1016/0009-9120(95)02015-2
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发表时间：
1996-02-01
影响因子：
2.8
通讯作者：
Yatscoff, RW
中科院分区：
文献类型：
--
作者：
Dias, VC;Yatscoff, RW
目的：评价一种体外方法预测口服新的免疫抑制药物，环孢素A（CsA）和雷帕霉素（RAPA）。方法：在这项研究中，我们报告的开发和表征的体外方法，研究的影响，车辆组成环孢素A（CsA）和雷帕霉素（PAPA）药物流出12天后融合，吸收人Caco-2肠上皮细胞单层。结果：0.5 μ Ci的H-3-CsA和0.05 μ Ci的C-14-RAPA在10 mg/L终浓度的溶剂中溶解后，其J（ab）CsA通量具有剂量依赖性、温度敏感性和高度极化性（J（ab）> J（ba））。CsA的溶媒为Neoral（R）Sandimmune（R），95%（v/v）乙醇/胎牛血清（乙醇/FBS）; PAPA的溶媒为聚乙二醇/二甲基乙酰胺（PEG/DMA）、聚山梨酯/Phosal PEG、乙醇/FBS。当测试Neoral（R）-CsA时，H-3-CsA的J（ab）通量最高，即使在孵育240 min后也几乎线性增加。当Sandimmune（R）-CsA或乙醇/FBS-CsA用作载体时，H-3-CsA的J（ab）通量较低，并在120 min时达到最大速率。RAPA作为车辆是最高的，并达到了最大速率120分钟，相比之下，聚山梨酯/Phosal PEG-RAPA车辆，这是显着lower.Conclusion：这些数据是一致的，这些ISD在体内报告的药代动力学在人类患者或在兔，使用相同的车辆在口服制剂。作为药物开发的一个组成部分，数据表明，所述体外系统可用于预测药物载体对体内吸收的影响。
Objective: To evaluate an in vitro method for predicting oral availability of novel immunosuppressive drugs, cyclosporine A (CsA) and rapamycin (RAPA).Methods: In this study, we report the development and characterization of an in vitro method to study the influence of vehicle composition on cyclosporine A (CsA) and rapamycin (PAPA) drug efflux across 12 days postconfluent, absorptive human Caco-2 intestinal epithelial cell monolayers. The apical-to-basal (J(ab)) and the basal-to-apical (J(ba)) fluxes of 0.5 mu Ci H-3-CsA or 0.05 mu Ci C-14-RAPA solubilized in a 10 mg/L final drug concentration in vehicle were measured.Results: The J(ab) CsA flux was found to be dose dependent, temperature sensitive, and highly polarized (J(ab) > J(ba)). For CsA the vehicles were Neoral(R) Sandimmune(R), 95% (v/v) ethanol/fetal bovine serum (ethanol/FBs); and for PAPA these were polyethylene glycol/dimethylacetamide (PEG/DMA), polysorbate/Phosal PEG, ethanol/FBS. When Neoral(R)-CsA was tested, the J(ab) flux of H-3-CsA was the highest and increased almost linearly even after an incubate time of 240 min. The J(ab) flux of H-3-CsA when Sandimmune(R)-CsA or ethanol/FBS-CsA were used as vehicle was lower and reached a maximal rate by 120 min. In contrast the J(ab) flux of C-14-RAPA using either PEG/DMA-RAPA or ethanol/FBS-RAPA as vehicle was highest and reached a maximal rate by 120 min, in contrast to the polysorbate/Phosal PEG-RAPA vehicle, which was significantly lower.Conclusion: These data are consistent with the pharmacokinetics of these ISD reported in vivo in human patients or in rabbits, using the same vehicles in the oral formulation. As an integral part of drug development, the data presented that an in vitro system as described may be useful in predicting the effect of drug vehicle on absorption in vivo.