A study of particulate intestinal absorption and hepatocellular uptake

Sanders, Edward B.; Ashworth, C. T.

doi:10.1016/0014-4827(61)90092-1

Cited by 134 publications

(28 citation statements)

References 10 publications

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“…Earlier workers postulated that the entire micellar particle might be taken up into the intestinal cell intact (8,9). However, more recent work from several laboratories has shown that the various constituent molecules carried in the micelle are absorbed at apparently independent rates suggesting that uptake must occur by some other mechanism (10)(11)(12).…”

Section: The Journal Of Clinical Investigation Volume 58 July 1976 97mentioning

confidence: 99%

The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell.

Westergaard¹,

Dietschy²

1976

J. Clin. Invest.

313

141

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A B s T R A C T Studies were undertaken to define the mechanism whereby bile acid facilitates fatty acid and cholesterol uptake into the intestinal mucosal cell. Initial studies showed that the rate of uptake (Jd) of several fatty acids and cholesterol was a linear function of the concentration of these molecules in the bulk phase if the concentration of bile acid was kept constant. In contrast, Jd decreased markedly when the concentration of bile acid was increased relative to that of the probe molecule but remained essentially constant when the concentration of both the bile acid and probe molecule was increased in parallel. In other studies Jd for lauric acid measured from solutions containing either 0 or 20 mM taurodeoxycholate and saturated with the fatty acid equaled 79.8±5.2 and 120.8±9.4 nmol[min-' 100 mg1, respectively: after correction for unstirred layer resistance, however, the former value equaled 113.5±7.1 nmol min-' 100 mg-'. Maximum values of Jd for the saturated fatty acids with 12, 16, and 18 carbons equaled 120.8±9.4, 24.1±3.2, and 13.6±+1.1 nmol min-' 100 mg-', respectively. These values essentially equaled those derived by multiplying the maximum solubility times the passive permeability coefficients appropriate for each of these compounds. The theoretical equations were then derived that define the expected behavior of Jd for the various lipids under these different experimental circumstances where the mechanism of absorption was assumed to occur either by uptake of the whole micelle, during interaction of the micelle with an infinite number of sites on the microvillus membrane or through a monomer Dr. Westergaard was a postdoctoral research fellow in gastroenterology while these studies were undertaken. His current address is Medical Department P, University Hospital, DK-2100 Copenhagen 0, Denmark. phase of lipid molecules in equilibrium with the micelle. The experimental results were consistent both qualitatively and quantitatively with the third model indicating that the principle role of the micelle in facilitating lipid absorption is to overcome unstirred layer resistance while the actual process of fatty acid and cholesterol absorption occurs through a monomer phase in equilibrium with the micelle.

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Section: The Journal Of Clinical Investigation Volume 58 July 1976 97mentioning

confidence: 99%

The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell.

Westergaard¹,

Dietschy²

1976

J. Clin. Invest.

313

141

View full text Add to dashboard Cite

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“…oral delivery | uptake mechanism B eginning in the 1960s, several groups (1)(2)(3)(4)(5)(6)(7) demonstrated that the small intestine could absorb microparticles with a diameter >1 μm, challenging dogma that the small intestine could only absorb small macromolecules. After this discovery, researchers began engineering microspheres (MSs) to deliver drugs with poor water solubility (8)(9)(10), poor gastrointestinal permeability (11), or poor oral bioavailability (8,9,(12)(13)(14)(15) to the small intestine.…”

mentioning

confidence: 99%

Unique insights into the intestinal absorption, transit, and subsequent biodistribution of polymer-derived microspheres

Reineke

Cho

Dingle

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Polymeric microspheres (MSs) have received attention for their potential to improve the delivery of drugs with poor oral bioavailability. Although MSs can be absorbed into the absorptive epithelium of the small intestine, little is known about the physiologic mechanisms that are responsible for their cellular trafficking. In these experiments, nonbiodegradable polystyrene MSs (diameter range: 500 nm to 5 μm) were delivered locally to the jejunum or ileum or by oral administration to young male rats. Following administration, MSs were taken up rapidly (≤5 min) by the small intestine and were detected by transmission electron microscopy and confocal laser scanning microscopy. Gel permeation chromatography confirmed that polymer was present in all tissue samples, including the brain. These results confirm that MSs (diameter range: 500 nm to 5 μm) were absorbed by the small intestine and distributed throughout the rat. After delivering MSs to the jejunum or ileum, high concentrations of polystyrene were detected in the liver, kidneys, and lungs. The pharmacologic inhibitors chlorpromazine, phorbol 12-myristate 13-acetate, and cytochalasin D caused a reduction in the total number of MSs absorbed in the jejunum and ileum, demonstrating that nonphagocytic processes (including endocytosis) direct the uptake of MSs in the small intestine. These results challenge the convention that phagocytic cells such as the microfold cells solely facilitate MS absorption in the small intestine.oral delivery | uptake mechanism B eginning in the 1960s, several groups (1-7) demonstrated that the small intestine could absorb microparticles with a diameter >1 μm, challenging dogma that the small intestine could only absorb small macromolecules. After this discovery, researchers began engineering microspheres (MSs) to deliver drugs with poor water solubility (8-10), poor gastrointestinal permeability (11), or poor oral bioavailability (8,9,(12)(13)(14)(15) to the small intestine. MS-based oral drug delivery systems (ODDSs) can be made from biodegradable polymers (12,(16)(17)(18), nondegradable polymers (19-21), and polysaccharides (22, 23) and can be engineered to carry polypeptides (18,24,25) and other molecules (26, 27). The motivation for using microparticulate-based ODDSs is to improve the oral bioavailability of drugs by enhancing their delivery and transit through the absorptive epithelium of the small intestine. This work may ultimately enable patients to take medications orally instead of relying on daily or weekly injections or other, less convenient routes of administration (28).More than five decades after Sanders and Ashworth discovered that the small intestine can engulf large particles (1), little is known today about the cellular mechanisms or physiologic pathways that facilitate the absorption, transit, and biodistribution of microparticles that are delivered to the small intestine. Nonetheless, the diverse physiology and multitude of cell types in the small intestine likely play a central role in these processes. The absorp...

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“…Herein, physicochemical parameters are the controlling factors, such as size, surface, lipophilicity, hydrophilicity, or polarity. Increased bioavailability using BS was explained by enhanced vesicle uptake and transport through the intestinal membrane (55), or the vesicle absorption by enterocytes through endocytosis (56)(57). BS were also detected to increase the paracellular permeation of CEF by a mucolytic effect and opening the tight junctions by binding to calcium ions (58).…”

Section: Discussionmentioning

confidence: 99%

Nanosized Liposomes Containing Bile Salt: A Vesicular Nanocarrier for Enhancing Oral Bioavailability of BCS Class III Drug

et al. 2017

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-PURPOSE: Liposomes have been studied as a colloidal carrier in drug delivery systems, especially for oral administration. However, their low structural integrity in the gut is still a major shortcoming. Membrane disruptive effects of physiological bile salts in the small intestine result in premature drug release prior to intestinal absorption. Thus, we analyzed the stabilizing effect of sodium deoxycholate when incorporated into nano-sized liposomes. METHOD: Cefotaxime-loaded liposomes were prepared with different sodium deoxycholate concentrations (3.75-30 mM) by rotary film evaporation followed by nanosize reduction. The physical integrity of liposomes was evaluated by monitoring cefotaxime leakage, particle sizes in different simulated physiological media. The oral bioavailability and pharmacokinetics of cefotaxime was assessed in rats (n = 6 per group) after single dose of drug-encapsulated in liposomes containing bile salt, drug in conventional liposomes, and cefotaxime solution (oral and intravenous). RESULTS: Simulated gastric fluid with low pH showed less effect on the stability of liposomes in comparison to media containing physiological bile salts. Liposomes containing 15 mM sodium deoxycholate were most stable in size and retained the majority of encapsulated cefotaxime even in fed state of simulated intestinal fluid being the most destructive media. Pharmacokinetics data showed an increase in Cmax and AUC0-inf in the following order: cefotaxime solution < conventional liposomes < liposomes made with bile salts. The total oral bioavailability of cefotaxime in liposomes containing bile salt was found to be 5-times higher compared to cefotaxime solution and twice as much as in conventional liposomes. CONCLUSION: Incorporation of bile salts, initially used as membrane permeation enhancer, also acted as a stabilizer against physiological bile salts. The nanosized liposomes containing sodium deoxycholate were able to reduce the leakage of encapsulated cefotaxime in the gut due to the improved vesicle stability and to enhance the oral bioavailability of acid-labile drugs up to 5-fold.

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A study of particulate intestinal absorption and hepatocellular uptake

Cited by 134 publications

References 10 publications

The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell.

The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell.

Unique insights into the intestinal absorption, transit, and subsequent biodistribution of polymer-derived microspheres

Nanosized Liposomes Containing Bile Salt: A Vesicular Nanocarrier for Enhancing Oral Bioavailability of BCS Class III Drug

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