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Cited by 82Drug Solubulity and Delivery SystemsAdvanced Drug Delivery SystemsDrug Transport and Resistance Mechanisms

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

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Keemink, Janneke, Mårtensson, Elin, Bergström, Christel A.S.·2019·Molecular Pharmaceutics
DOI 10.1021/acs.molpharmaceut.8b00811PMC PMC6437649
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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.

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  • The two-stage model correctly predicted the rank order of in vivo performance in pigs of three fenofibrate lipid-based drug delivery systems and carvedilol absorption in dogs after administration as dissolved in lipid-based drug delivery systems or co-administered with lipid-based drug delivery systems.

    “Thus, the twostage model correctly predicted the rank order of the in vivo performance in pigs of three fenofibrate LBDDS and the carvedilol absorption in dogs after administration as dissolved in LBDDS or co-administered with LBDDS (Keemink et al., 2019; Griffin et al., 2014; Alskär et al., 2019).”

    From Exploring impact of supersaturated lipid-based drug delivery systems of celecoxib on in vitro permeation across PermeapadⓇ membrane and in vivo absorption (2020) · cites this paper as Keemink et al., 2019

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Cited by

Sorted by citations

Authors
Keemink, J., Mårtensson, E., & Bergström, C. A. S.
Affiliations
  • Uppsala University (SE)
  • Uppsala University , , Uppsala Biomedical Center , P.O. Box 580, ,
ORCID
Keemink, Janneke
Venue
Molecular Pharmaceutics
Publisher
American Chemical Society (ACS)
Published
2019-01-10
Volume
16
Issue
3
Pages
921-930
ISSN
  • 1543-8384 (ISSN-L)
  • 1543-8392
DOI
10.1021/acs.molpharmaceut.8b00811
PMC
PMC6437649
OpenAlex
W2909432337
Cited by
82
References
1
Citations by year
2026: 6 · 2025: 12 · 2024: 9 · 2023: 9 · 2022: 8 · 2021: 11 · 2020: 20 · 2019: 7
FWCI
4.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Pharmaceutics (publishedVersion, other-oa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
Funders
  • H2020 European Research Council (638965)
  • Vetenskapsrådet (2014-3309)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
lipid-based formulations, intestinal digestion, drug absorption, Caco-2 cell monolayers, sink conditions, immobilized lipase, fenofibrate, danazol, in vitro-in vivo correlation, drug permeation, supersaturation, poorly water-soluble drugs, drug delivery
MeSH terms
Administration, Oral, Chemistry, Pharmaceutical, Danazol, Digestion, Drug Compounding, Pharmaceutical Preparations, Humans, Intestinal Absorption, Lipase, Lipids, Lipolysis, Membranes, Artificial, Models, Biological, Fenofibrate, Solubility, Caco-2 Cells, Absorption, Physicochemical, In Vitro Techniques

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