Avoidance of food effect on oral absorption profile of itraconazole by self-micellizing solid dispersion approach
Avoidance of food effect on oral absorption profile of itraconazole by self-micellizing solid dispersion approach
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DOI：
10.1016/j.dmpk.2017.06.001
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发表时间：
2017-10-01
影响因子：
2.1
通讯作者：
Onoue, Satomi
中科院分区：
文献类型：
--
作者：
Kojo, Yoshiki;Kobayashi, Kanako;Onoue, Satomi
本研究采用自胶束固体分散体（SMSD）方法避免伊曲康唑（itraconazole， ITZ）在高脂肪膳食摄入后引起的药代动力学转变。观察SMSD/ITZ在模拟胃液（SGF）和模拟肠液（SIF）中的溶出行为。为了评估食物对肠毒素口服吸收谱的影响，我们对空腹和高脂肪膳食喂养的大鼠口服给药肠毒素样品进行了药代动力学研究。晶体ITZ在供能态SGF （FeSSGF）中的溶出量是快速态SGF （FaSSGF）的9.0倍，而在SMSD/ITZ中的溶出量在FeSSGF和FaSSGF之间没有显著差异。在进料态和快态SIF中，SMSD/ITZ的溶出变化减小，这可能是由于食物效应抑制了ITZ的溶出行为。高脂饲料喂养大鼠口服结晶ITZ后，其口服生物利用度比空腹大鼠高14倍。相比之下，口服剂量的SMSD/ITZ在喂养大鼠中表现出有限的药代动力学行为转变，无论食物摄入量如何，这是因为即使在禁食条件下，ITZ的溶解行为也有所改善。SMSD技术可以作为一种有效的剂量选择，使其具有一致的口服吸收和临床效果。(c) 2017年，由爱思唯尔有限公司代表日本异种生物研究学会出版。
The present study was aimed to avoid pharmacokinetic transitions of itraconazole (ITZ) evoked by high-fat meal intake by employing a self-micellizingsolid dispersion (SMSD) approach. The dissolution behavior of SMSD/ITZ was assessed in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). To evaluate the food effect on the oral absorption profile of ITZ, a pharmacokinetic study was conducted on orally-dosed ITZ samples in fasted and high-fat meal-fed rats. Crystalline ITZ showed a 9.0-fold higher dissolution amount of ITZ in fed-state SGF (FeSSGF) than in fasted-state SGF (FaSSGF), whereas there was no significant difference in the dissolution amount of ITZ in SMSD/ITZ between FeSSGF and FaSSGF. In fed-and fasted-state SIF, SMSD/ITZ exhibited reduced variation of ITZ dissolution, possibly leading to suppression of the food effect on the dissolution behavior of ITZ. After the oral administration of crystalline ITZ to high-fat meal-fed rats, the oral bioavailability of ITZ was 14-fold higher than that in fasted rats. In contrast, orally-dosed SMSD/ITZ in fed rats exhibited limited transition of pharmacokinetic behavior regardless of food intake due to the improvement in the dissolution behavior of ITZ even under fasted conditions. SMSD technology could be an efficacious dosage option for the consistent oral absorption and clinical outcomes of ITZ. (c) 2017, Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.