Maximum tolerated dose and toxicity evaluation of orally administered docetaxel granule in mice.
Maximum tolerated dose and toxicity evaluation of orally administered docetaxel granule in mice.
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小鼠口服多西紫杉醇颗粒的最大耐受剂量及毒性评价。
DOI：
10.1016/j.toxrep.2024.04.001
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发表时间：
2024
影响因子：
--
通讯作者：
Zhang,Jinmin
中科院分区：
文献类型：
--
作者：
Dong,Xiaowei;Zhang,Jinmin
化疗药物的口服递送是最有利和优选的给药途径。然而，由于溶解性和/或渗透性差，大多数化疗药物通过静脉内给药。多西他赛（DTX）是一种有效的化疗药物，可抑制微管解聚，并广泛用于治疗多种癌症。DTX是高度亲脂性的，不溶于水;因此，50%的聚山梨酯80可能会引起超敏反应，并减少肿瘤组织的药物摄取，用于市售DTX注射液中溶解DTX。最大耐受剂量（MTD）和毒性对于确定临床前研究中的参数和预测临床试验中的人体剂量是重要的。然而，尽管已经报道了各种口服DTX制剂，但尚未研究口服DTX制剂的MTD和毒性。我们以前开发了口服DTX颗粒，并证明其抑制肿瘤生长的能力。本研究旨在系统测定口服DTX颗粒剂在小鼠体内的最大耐受剂量（MTD）和组织分布，并评价其毒性。口服DTX颗粒剂的毒性和吸收存在性别差异。DTX颗粒的MTD测定为雌性小鼠50 mg/kg和雄性小鼠25 mg/kg。然而，雌性小鼠的组织吸收高于雄性小鼠。在很高的剂量（400 mg/kg）下，口服DTX颗粒可引起肾损伤，但对肝和肺无影响。本研究为今后口服DTX制剂治疗癌症的临床前研究和临床应用提供了基础数据。
Oral delivery of chemotherapy drugs is the most favorable and preferred route of drug administration. However, because of poor solubility and/or permeability, most chemotherapy drugs are given by intravenous administration. Docetaxel (DTX) is a potent chemotherapy drug that inhibits microtubular depolymerization and is widely used to treat numerous cancers. DTX is highly lipophilic and insoluble in water; thus, 50% polysorbate 80, which may cause hypersensitivity reactions and reduce drug uptake by tumor tissue, is used in the commercial DTX injection to dissolve DTX. Maximum tolerated dose (MTD) and toxicity are important to determine parameters in preclinical studies and to predict human dose in clinical trials. However, MTD and toxicity of oral DTX formulations have not been studied although various oral DTX formulations have been reported. We have previously developed oral DTX granule and demonstrated its ability to inhibit tumor growth. In this study, we aimed to systemically measure MTD and tissue distribution and evaluate the toxicity of oral DTX granule in mice. Oral DTX granule showed sex differences in toxicity and absorption. The MTD of DTX granule was determined at 50 mg/kg for female mice and 25 mg/kg for male mice. However, female mice had higher tissue absorption than male mice. At a very high dose (400 mg/kg), oral DTX granule induced kidney damage but did not influence the liver and the lungs. The study provides the fundamental data for future preclinical studies and clinical application of oral DTX formulations for cancers.