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Lipolysis-Permeation Setup for Simultaneous Study of Digestion and Absorption in Vitro.

ABSTRACT: Lipid-based formulations (LBFs) are a delivery strategy to enhance intestinal absorption of poorly water-soluble drugs. LBF performance is typically evaluated by in vitro lipolysis studies, but these do not accurately predict the in vivo performance. One possible reason is the absence of an absorptive membrane driving sink conditions in the serosal compartment. To explore the impact of absorption under sink conditions on the performance evaluation, we developed a lipolysis-permeation setup that allows simultaneous investigation of intestinal digestion of an LBF and drug absorption. The setup consists of two chambers, an upper one for digestion (luminal), and a lower, receiving one (serosal), separated by a Caco-2 monolayer. Digestions were performed with immobilized lipase, instead of the pancreatic extract typically used during lipolysis, since the latter has proven incompatible with Caco-2 cells. Danazol-loaded LBFs were used to develop the setup, and fenofibrate-loaded LBFs were used to establish an in vitro in vivo correlation. As in regular lipolysis studies, our setup allows for the evaluation of (i) the extent of digestion and (ii) drug distribution in different phases present during lipolysis of drug-loaded LBFs (i.e., oil, aqueous, and solid phase). In addition, our setup can determine drug permeation across Caco-2 monolayers and hence, the absorptive flux of the compound. The presence of the absorptive monolayer and sink conditions tended to reduce aqueous drug concentrations and supersaturation in the digestion chamber. The drug transfer across the Caco-2 membrane accurately reflected in vivo drug exposure upon administration of three different LBFs loaded with fenofibrate, where the traditional lipolysis setup failed to predict in vivo performance. As the new setup reflects the dynamic processes occurring in the gastrointestinal tract, it is a valuable tool that can be used in the development of LBFs prior to in vivo studies.

SUBMITTER: Keemink J

PROVIDER: S-EPMC6437649 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Lipolysis-Permeation Setup for Simultaneous Study of Digestion and Absorption in Vitro.

Keemink Janneke J Mårtensson Elin E Bergström Christel A S CAS

Molecular pharmaceutics 20190129 3

Lipid-based formulations (LBFs) are a delivery strategy to enhance intestinal absorption of poorly water-soluble drugs. LBF performance is typically evaluated by in vitro lipolysis studies, but these do not accurately predict the in vivo performance. One possible reason is the absence of an absorptive membrane driving sink conditions in the serosal compartment. To explore the impact of absorption under sink conditions on the performance evaluation, we developed a lipolysis-permeation setup that ...[more]

PMID: 30628771

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Project description:Nanoscale materials derived from natural biopolymers like cellulose and chitosan have many potentially useful agri-food and oral drug delivery applications. Because of their large and potentially bioactive surface areas and other unique physico-chemical properties, it is essential when evaluating their toxicological impact to assess potential effects on the digestion and absorption of co-ingested nutrients. Here, the effects of cellulose nanofibers (CNF), cellulose nanocrystals (CNC), and chitosan nanoparticles (Chnp) on the digestion and absorption of carbohydrates were studied. Starch digestion was assessed by measuring maltose released during simulated digestion of starch solutions. Glucose absorption was assessed by measuring translocation from the resulting digestas across an in vitro transwell tri-culture model of the small intestinal epithelium and calculating the area under the curve increase in absorbed glucose, analogous to the glycemic index. At 1% w/w, CNF and Chnp had small but significant effects (11% decrease and 14% increase, respectively) and CNC had no effect on starch hydrolysis during simulated digestion of a 1% w/w rice starch solution. In addition, at 2% w/w CNC had no effect on amylolysis in 1% solutions of either rice, corn, or wheat starch. Similarly, absorption of glucose from digestas of starch solutions (i.e., from maltose), was unaffected by 1% w/w CNF or CNC, but was slightly increased (10%, p<0.05) by 1% Chnp, possibly due to the slightly higher maltose concentration in the Chnp-containing digestas. In contrast, all of the test materials caused sharp increases (~1.2, 1.5, and 1.6 fold for CNC, CNF, and Chnp, respectively) in absorption of glucose from starch-free digestas spiked with free glucose at a concentration corresponding to complete hydrolysis of 1% w/w starch. The potential for ingested cellulose and chitosan nanomaterials to increase glucose absorption could have important health implications. Further studies are needed to elucidate the mechanisms underlying the observed increases and to evaluate the potential glycemic effects in an intact in vivo system.

Dataset Information

Lipolysis-Permeation Setup for Simultaneous Study of Digestion and Absorption in Vitro.

Publications

Lipolysis-Permeation Setup for Simultaneous Study of Digestion and Absorption in Vitro.

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