title: Transport of a novel anti-cancer agent, fenretinide across Caco-2 monolayers.
abstract: Fenretinide is a synthetic retinoid with chemotherapeutic activity against various malignancies. Upon oral administration to animals, fenretinide was found to be incompletely absorbed and excreted primarily in feces. The purpose of this study was to determine the possible reasons for poor oral absorption of fenretinide using Caco-2 cell monolayers. To achieve this purpose, a solid dispersion of fenretinide with Povidone K25 was used. The apparent permeability coefficient (P(app)) of fenretinide across Caco-2 monolayers in the presence of bovine serum albumin (BSA) in the receiver was determined. Apical to basolateral (AP-BL) and basolateral to apical (BL-AP) flux studies were performed to determine the role of an efflux mechanism. In the presence of 4% BSA in the receiver, the P(app) was found to be (8.8 +/- 0.5) x 10(-8) cm/sec. The AP-BL flux increased linearly with an increase in fenretinide concentration (125-640 microM) in the presence of 4% BSA in the receiver. Efflux and paracellular pathways played an insignificant role in the permeability of fenretinide. A significant amount of drug, approximately 13-15% of the initial amount accumulated in the cell membrane. The amount of fenretinide in the donor decreased by 16% over a 3 h period. However, only 0.12% of the initial amount was found in the receiver. Also, the P(app) increased with an increase in plasma protein concentration in the receiver. On the basis of these results, the poor permeability of fenretinide can be attributed to its accumulation in the lipophilic cell membrane and poor partitioning into the receiver medium.
authors.affiliation: Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA 95211, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Kokate
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Bhaskara
authors.initials: B
authors.lastname: Jasti
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D002626:Chemistry, Pharmaceutical; D004058:Diffusion; D017097:Electric Impedance; D005079:Excipients / Q000737:chemistry; D017313:Fenretinide / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D011205:Povidone / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000378:metabolism; D012995:Solubility; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D005079:Excipients; D017313:Fenretinide; D012710:Serum Albumin, Bovine; D011205:Povidone