Maximum tolerated dose and toxicity evaluation of orally administered docetaxel granule in mice
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 dep...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-06-01
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| Series: | Toxicology Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214750024000398 |
| _version_ | 1797214872284430336 |
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| author | Xiaowei Dong Jinmin Zhang |
| author_facet | Xiaowei Dong Jinmin Zhang |
| author_sort | Xiaowei Dong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T11:21:04Z |
| format | Article |
| id | doaj.art-1e68cb10fc474e47951917caa418c785 |
| institution | Directory Open Access Journal |
| issn | 2214-7500 |
| language | English |
| last_indexed | 2024-04-24T11:21:04Z |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Toxicology Reports |
| spelling | doaj.art-1e68cb10fc474e47951917caa418c7852024-04-11T04:41:17ZengElsevierToxicology Reports2214-75002024-06-0112430435Maximum tolerated dose and toxicity evaluation of orally administered docetaxel granule in miceXiaowei Dong0Jinmin Zhang1Correspondence to: Department of Pharmaceutical Sciences, College of Pharmacy, University of North Texas System, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.; Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USADepartment of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USAOral 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.http://www.sciencedirect.com/science/article/pii/S2214750024000398DocetaxelToxicityMaximum tolerated doseSex differenceTissue distribution |
| spellingShingle | Xiaowei Dong Jinmin Zhang Maximum tolerated dose and toxicity evaluation of orally administered docetaxel granule in mice Toxicology Reports Docetaxel Toxicity Maximum tolerated dose Sex difference Tissue distribution |
| title | Maximum tolerated dose and toxicity evaluation of orally administered docetaxel granule in mice |
| title_full | Maximum tolerated dose and toxicity evaluation of orally administered docetaxel granule in mice |
| title_fullStr | Maximum tolerated dose and toxicity evaluation of orally administered docetaxel granule in mice |
| title_full_unstemmed | Maximum tolerated dose and toxicity evaluation of orally administered docetaxel granule in mice |
| title_short | Maximum tolerated dose and toxicity evaluation of orally administered docetaxel granule in mice |
| title_sort | maximum tolerated dose and toxicity evaluation of orally administered docetaxel granule in mice |
| topic | Docetaxel Toxicity Maximum tolerated dose Sex difference Tissue distribution |
| url | http://www.sciencedirect.com/science/article/pii/S2214750024000398 |
| work_keys_str_mv | AT xiaoweidong maximumtolerateddoseandtoxicityevaluationoforallyadministereddocetaxelgranuleinmice AT jinminzhang maximumtolerateddoseandtoxicityevaluationoforallyadministereddocetaxelgranuleinmice |