Abstract:
:Currently, the screening of new drug candidates for intestinal permeation is typically based on in vitro models which give no information regarding regional differences along the gut. When evaluation of intestinal permeability by region is undertaken, two preclinical rat models are commonly used, the Ussing chamber method and single-pass intestinal perfusion (SPIP). To investigate the robustness of in vivo predictions of human intestinal permeability, a set of four model compounds was systematically investigated in both these models, using tissue specimens and segments from the jejunum, ileum, and colon of rats from the same genetic strain. The influence of luminal pH was also determined at two pH levels. Ketoprofen had high and enalaprilat had low effective (Peff) and apparent (Papp) permeability in all three regions and at both pH levels. Metoprolol had high Peff in all regions and at both pHs and high Papp at both pHs and in all regions except the jejunum, where Papp was low. Atenolol had low Peff in all regions and at both pHs, but had high Papp at pH 6.5 and low Papp at pH 7.4. There were good correlations between these rat in situ Peff (SPIP) and human in vivo Peff determined previously for the same compounds by both intestinal perfusion of the jejunum and regional intestinal dosing. The results of this study indicate that both investigated models are suitable for determining the regional permeability of the intestine; however, the SPIP model seems to be the more robust and accurate regional permeability model.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Roos C,Dahlgren D,Sjögren E,Tannergren C,Abrahamsson B,Lennernäs Hdoi
10.1021/acs.molpharmaceut.7b00279subject
Has Abstractpub_date
2017-12-04 00:00:00pages
4252-4261issue
12eissn
1543-8384issn
1543-8392journal_volume
14pub_type
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