Transport of Cosalane—A Highly Lipophilic Novel Anti‐HIV Agent—Across Caco‐2 Cell Monolayers

Pal, Dhananjay; Udata, Chandrasekhar; Mitra, Ashim K.

doi:10.1002/(sici)1520-6017(200006)89:6<826::aid-jps15>3.0.co;2-4

Cited by 20 publications

(13 citation statements)

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“…Lack of detectable quantities of fenretinide transport in in vitro permeation across rat everted gut sacs studies and appearance of dark yellow color (fenretinide is yellow) due to extensive accumulation of fenretinide confirmed its accumulation (data not shown). In a similar study, metabolism, paracellular transport and efflux did not contribute to the poor permeation of cosalane; instead, cosalane permeability across Caco-2 cells was limited by accumulation in the cell membrane and poor partitioning into the receiver [23]. Sawada et al also state that poor permeability of highly lipophilic compounds is due to limited desorption from the receiver-side membrane into the buffer, which is further restricted by in vitro assays with a limited volume of receiver [31].…”

Section: Accumulation Of Fenretinide In the Cell Monolayersupporting

confidence: 82%

“…Sawada et al also state that poor permeability of highly lipophilic compounds is due to limited desorption from the receiver-side membrane into the buffer, which is further restricted by in vitro assays with a limited volume of receiver [31]. In accordance with lipophilic compounds like chlorpromazine [28], pyrimidine-based antioxidants [31], and cosalane [23], accumulation in the cell membrane might be playing a role in the poor permeability of fenretinide. As further proof for accumulation-limited transport of fenretinide, disappearance (from donor, AP) and appearance (in receiver, BL) studies of fenretinide across the monolayer demonstrate a distinct difference between the uptake and appearance profiles of fenretinide (Fig.…”

Section: Accumulation Of Fenretinide In the Cell Monolayermentioning

confidence: 80%

“…However, even at a BSA concentration of 4%, fenretinide exhibited poor permeability (8.8 × 10 −8 cm/sec), which might be due to poor partitioning of the highly lipophilic moiety between the cell membrane and the receiving medium. A similar observation was reported for cosalane, a highly lipophilic anti-HIV agent (log P = 6.8), which had a very low P app (4.49 × 10 −8 cm/sec) in the presence of 1% BSA [23].…”

Section: Permeability Of Fenretinide In the Presence Of Plasma Proteinsmentioning

confidence: 99%

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Transport of a novel anti-cancer agent, fenretinide across Caco-2 monolayers

Kokate

Jasti

2006

Invest New Drugs

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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.

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Section: Accumulation Of Fenretinide In the Cell Monolayersupporting

confidence: 82%

Section: Accumulation Of Fenretinide In the Cell Monolayermentioning

confidence: 80%

Section: Permeability Of Fenretinide In the Presence Of Plasma Proteinsmentioning

confidence: 99%

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Transport of a novel anti-cancer agent, fenretinide across Caco-2 monolayers

Kokate

Jasti

2006

Invest New Drugs

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“…Since FBS contains about 2.5-5% BSA (FBS certificate of analysis, Life and Technologies, Inc.), medium with 10% FBS (0.25-0.5% of BSA) showed less effect on naphthalene transport than 10% BSA. Our findings also agree well with the study on transporting of cosalane into Caco-2 cells (38). They reported that increasing concentration of BSA also resulted in reduced cellular accumulation of cosalane.…”

Section: Discussionsupporting

confidence: 93%

Prediction of Naphthalene Bioaccumulation Using an Adipocyte Cell Line Model

Viravaidya

Shuler

2002

Biotechnology Progress

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A long-term goal of this research is to develop an in vitro model to study the metabolism, distribution, and fate of chemicals or pharmaceuticals in animals and humans. An important component of such a system is an in vitro model to study bioaccumulation of specific chemicals in adipose tissue. Due to the difficulties in maintaining primary adipocytes in culture and conducting reproducible experiments, transformed adipocyte cell lines have been used as an alternative. In this paper, several rodent preadipocyte cell lines (3T3-L1, 3T3-F442A, and TA1 cells) that differentiate into adipocytes when exposed to the appropriate stimuli are tested as an investigative tool to study naphthalene accumulation. The in vitro model is tested by comparison of its performance to that of primary adipocytes. All the experimental evidence supports the hypothesis that naphthalene accumulation is primarily dependent on the level of intracellular lipid. Furthermore, the level of naphthalene bioaccumulation is linearly correlated with the amount of triglyceride content with the slope of 37.7 +/- 0.5 microg of naphthalene/(mg of triglyceride). Indomethacin/dexamethasone/insulin are shown to be more effective in promoting preadipocyte differentiation than methylisobutylxanthine/dexamethasone/insulin. Additionally, external factors, such as the presence of albumin and serum in the medium, affect the cellular naphthalene uptake by decreasing the amount of naphthalene transported into fat cells. Among the three cell lines tested, 3T3-L1 adipocytes accumulated the highest intracellular lipid and, hence, yielded the highest level of naphthalene accumulation. Its ability to accumulate naphthalene is comparable to that of primary adipocytes. The 3T3-L1 adipocyte model is appropriate for studying the bioaccumulation of xenobiotics that are aromatic hydrocarbons.

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“…All values obtained were the means of three independent experiments. Apparent permeability coefficients (P app ) of the analysed compounds were calculated according to the following equation (Artursson and Karlson, 1991;Pal et al, 2000;Raje et al, 2003):…”

Section: Permeation Studies Across Cell Monolayersmentioning

confidence: 99%