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Int. J. Mol. Sci. 2014, 15(5), 7199-7212; doi:10.3390/ijms15057199
Article

Study on Biopharmaceutics Classification and Oral Bioavailability of a Novel Multikinase Inhibitor NCE for Cancer Therapy

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Received: 25 February 2014 / Revised: 26 March 2014 / Accepted: 3 April 2014 / Published: 25 April 2014
(This article belongs to the Section Molecular Pathology)
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Abstract

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 × 104 mg·min−1·cm2. 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.
Keywords: biopharmaceutics classification system; intrinsic dissolution rate; permeability; bioavailability; multikinase inhibitor biopharmaceutics classification system; intrinsic dissolution rate; permeability; bioavailability; multikinase inhibitor
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Yang, Y.; Fan, C.-M.; He, X.; Ren, K.; Zhang, J.-K.; He, Y.-J.; Yu, L.-T.; Zhao, Y.-L.; Gong, C.-Y.; Zheng, Y.; Song, X.-R.; Zeng, J. Study on Biopharmaceutics Classification and Oral Bioavailability of a Novel Multikinase Inhibitor NCE for Cancer Therapy. Int. J. Mol. Sci. 2014, 15, 7199-7212.

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