Use of a dynamic in vitro lipolysis model to rationalize oral formulation development for poor water soluble drugs:: Correlation with in vivo data and the relationship to intra-enterocyte processes in rats
Use of a dynamic in vitro lipolysis model to rationalize oral formulation development for poor water soluble drugs:: Correlation with in vivo data and the relationship to intra-enterocyte processes in rats
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DOI：
10.1007/s11095-006-9054-x
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发表时间：
2006-09-01
影响因子：
3.7
通讯作者：
Hoffman, Amnon
中科院分区：
文献类型：
--
作者：
Dahan, Arik;Hoffman, Amnon
目的。探讨不同脂质溶液中亲脂化合物的体外增溶过程与体内口服生物利用度的相关性。特别是，评估肠内细胞过程（代谢和淋巴吸收）对这种相关性的影响。材料与方法。采用动态体外脂解模型，测定了长链（LCT）、中链（MCT）和短链（SCT）甘油三酯溶液中黄体酮和维生素D-3的溶出度。在大鼠体内研究了所试制剂中药物的绝对口服生物利用度。在环己亚胺（3mg /kg）诱导淋巴运输阻塞后，还检测了维生素D-3的生物利用度。动态体外脂解实验表明，黄体酮和维生素D-3的代谢顺序为MCT b> LCT b> SCT。黄体酮的生物利用度与体外数据相关，尽管其显著的全身前代谢。对于维生素D-3，获得了LCT b> MCT b> SCT的体内性能等级。然而，当淋巴运输被阻断时，维生素D-3的生物利用度与体外数据相关。体外脂解模型可用于优化口服脂质配方，即使在肠道前系统代谢的情况下也是如此。然而，当淋巴运输是一个重要的吸收途径时，体外脂肪分解数据可能不能预测实际的体内吸收。
Purpose. To examine the correlation between the in vitro solubilization process of lipophilic compounds from different lipid solutions and the corresponding in vivo oral bioavailability data. In particular, to assess the influence of intra-enterocyte processes (metabolism and lymphatic absorption) on this correlation.Materials and Methods. The dissolution of progesterone and vitamin D-3 in long (LCT), medium (MCT) and short (SCT) chain triglyceride solutions were tested in a dynamic in vitro lipolysis model. The absolute oral bioavailability of the drugs from the tested formulations was investigated in rats. Vitamin D-3 bioavailability was also examined following lymphatic transport blockage induced by cycloheximide (3 mg/kg).Results. The dynamic in vitro lipolysis experiments indicated a rank order of MCT > LCT > SCT for both progesterone and vitamin D-3. The bioavailability of progesterone correlated with the in vitro data, despite its significant pre-systemic metabolism. For vitamin D-3, an in vivo performance rank order of LCT > MCT > SCT was obtained. However, when the lymphatic transport was blocked the bioavailability of vitamin D-3 correlated with in vitro data.Conclusions. The in vitro lipolysis model is useful for optimization of oral lipid formulations even in the case of pre-systemic metabolism in the gut. However, when lymphatic transport is a significant route of absorption, the in vitro lipolysis data may not be predictive for actual in vivo absorption.