Femetinide is a synthetic retinoid with chemotherapeutic activity against various malignancies. After oral administration to animals, femetinide was found to be incompletely absorbed and excreted primarily in feces. The purpose of this study was to investigate the mechanism(s) responsible for the transport of femetinide across Caco-2 cell monolayers with an aim to determine the possible reasons for poor oral absorption of fenretinide. Fenretinide was found to be highly lipophilic (log P = 7.4) and practically insoluble in water. The water solubility of fenretinide was enhanced by formulating it as a Povidone K 25 solid dispersion. The Transepithelial Electrical Resistance (TEER) and antipyrine permeability (transcellular marker) were not affected after treatment with 0.5% PVP K 25 on the apical side. The apparent permeability coefficient (Papp) of fenreti nide was extremely low [(8.8 ± 0.5) x 10-8 cm/sec] even in the presence of 4% bovine serum albumin (BSA) in the receiver. The apical to basolateral (AP-BL) transport appeared linearly related to the fenretinide concentration ( 125-640 μM), thereby indicating that femetinide penneates the Caco-2 monolayer by passive diffusion within the concentration range. Transport studies at different donor (apical) pH conditions (6.0 or 7.4) revealed that no pH-dependent transporters were involved in the apical to basolateral transport of fenretinide across the Caco-2 monolayer. Efflux transporters like P-glycoprotein (P-gp) and the paracellular pathway did not play a significant role on the permeability of fenretinide.
The partitioning of highly lipophilic molecules like fenretinicle from the cell membrane into the receiver depends on the composition of the receiving medium. The permeability of fenretinide increased with an increase in the bovine serum albumin (BSA) concentration (0 to 4 %) in the receiver. The addition of RBP to the receiving medium containing 4 % BSA increased the permeability of femetinicle clue to a greater binding affinity of fenretinicle for RBP. Significant amount (13-15% of the initial amount) of drug was found to accumulate in the cell membrane. The permeation of femetinide in Caco-2 monolayers is limited due to extensive accumulation in the cell membrane and poor partitioning from the cell membrane into the receiver medium.
| Identifer | oai:union.ndltd.org:pacific.edu/oai:scholarlycommons.pacific.edu:uop_etds-1600 |
| Date | 01 January 2004 |
| Creators | Kokate, Amit |
| Publisher | Scholarly Commons |
| Source Sets | University of the Pacific |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | University of the Pacific Theses and Dissertations |
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