**5. Conclusions**

Regional-dependent permeability throughout the small intestine was evident for furosemide. The permeability of furosemide gradually decreases throughout the small intestine as a function of the pH change in the intestinal lumen. However, at any point throughout the small intestine, furosemide exhibited significantly lower permeability than the benchmark of metoprolols permeability in the jejunum, which may explain the incomplete absorption of the drug. We propose that, for a drug to be classified as BCS low-permeability, its intestinal permeability should not match/exceed the low/high class benchmark anywhere throughout the intestinal tract, as well as is not restricted necessarily to the jejunum. Nevertheless, low-permeable drugs should not be treated as 'unfavorable' by default; instead, therapeutic potential and suitable formulation strategies should be considered on a case-by-case basis, taking into account the overall results of in-vitro, in-vivo, and in-silico testing, throughout the entire gastrointestinal tract.

**Author Contributions:** M.M., M.Z., I.R., S.C. and A.D. worked on conceptualization, methodology, investigation, analyzed the data, and outlined the manuscript. S.C. worked on software investigation. Writing: S.C., A.D. and M.M. prepared the original draft of the article, and M.Z. and I.R. contributed to the writing-review and editing of the full version. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
