Study on Biopharmaceutics Classification and Oral Bioavailability of a Novel Multikinase Inhibitor NCE for Cancer Therapy
| Autor: | Yinglan Zhao, Xuan He, Yang Yang, Yu Zheng, Jin-Kun Zhang, Ke Ren, Chun-Mei Fan, Ying-Ju He, Luoting Yu, Changyang Gong, Xiangrong Song, Jun Zeng |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Drug
Male media_common.quotation_subject Administration Oral Biological Availability Pharmacology Catalysis Intestinal absorption Article Biopharmaceutics Inorganic Chemistry lcsh:Chemistry Rats Sprague-Dawley Dogs Neoplasms medicine Animals biopharmaceutics classification system Theophylline Physical and Theoretical Chemistry Solubility Intestinal Mucosa Molecular Biology lcsh:QH301-705.5 Protein Kinase Inhibitors Spectroscopy media_common Intestinal permeability Chemistry Organic Chemistry General Medicine medicine.disease Biopharmaceutics Classification System Computer Science Applications Bioavailability Rats lcsh:Biology (General) lcsh:QD1-999 Intestinal Absorption intrinsic dissolution rate Administration Intravenous permeability bioavailability multikinase inhibitor medicine.drug |
| Zdroj: | International Journal of Molecular Sciences Volume 15 Issue 5 Pages 7199-7212 International Journal of Molecular Sciences, Vol 15, Iss 5, Pp 7199-7212 (2014) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms15057199 |
| Popis: | Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl) benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE) were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR) of NCE were estimated in different phosphate buffers. Effective intestinal permeability (Peff) of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability) and ranitidine (low permeability) were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 μg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10−4 mg·min−1·cm−2. The Peff value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates. |
| Databáze: | OpenAIRE |
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