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dc.creatorMarković, Milica
dc.creatorZur, Moran
dc.creatorRagatsky, Inna
dc.creatorCvijić, Sandra
dc.creatorDahan, Arik
dc.date.accessioned2020-12-15T13:34:44Z
dc.date.available2020-12-15T13:34:44Z
dc.date.issued2020
dc.identifier.issn1999-4923
dc.identifier.urihttps://farfar.pharmacy.bg.ac.rs/handle/123456789/3753
dc.description.abstractBiopharmaceutical classification system (BCS) class IV drugs (low-solubility low-permeability) are generally poor drug candidates, yet, ~5% of oral drugs on the market belong to this class. While solubility is often predictable, intestinal permeability is rather complicated and highly dependent on many biochemical/physiological parameters. In this work, we investigated the solubility/permeability of BCS class IV drug, furosemide, considering the complexity of the entire small intestine (SI). Furosemide solubility, physicochemical properties, and intestinal permeability were thoroughly investigated in-vitro and in-vivo throughout the SI. In addition, advanced in-silico simulations (GastroPlus®) were used to elucidate furosemide regional-dependent absorption pattern. Metoprolol was used as the low/high permeability class boundary. Furosemide was found to be a low-solubility compound. Log D of furosemide at the three pH values 6.5, 7.0, and 7.5 (representing the conditions throughout the SI) showed a downward trend. Similarly, segmental-dependent in-vivo intestinal permeability was revealed; as the intestinal region becomes progressively distal, and the pH gradually increases, the permeability of furosemide significantly decreased. The opposite trend was evident for metoprolol. Theoretical physicochemical analysis based on ionization, pKa, and partitioning predicted the same trend and confirmed the experimental results. Computational simulations clearly showed the effect of furosemide’s regional-dependent permeability on its absorption, as well as the critical role of the drug’s absorption window on the overall bioavailability. The data reveals the absorption window of furosemide in the proximal SI, allowing adequate absorption and consequent effect, despite its class IV characteristics. Nevertheless, this absorption window so early on in the SI rules out the suitability of controlled-release furosemide formulations, as confirmed by the in-silico results. The potential link between segmental-dependent intestinal permeability and adequate oral absorption of BCS Class IV drugs may aid to develop challenging drugs as successful oral products.en
dc.publisherMDPI AG
dc.rightsopenAccess
dc.sourcePharmaceutics
dc.subjectBiopharmaceutics
dc.subjectBCS class IV drugs
dc.subjectFurosemide
dc.subjectIntestinal absorption
dc.subjectOral drug delivery
dc.subjectPhysiologically-based pharmacokinetic (PBPK) modeling
dc.subjectSegmental-dependent intestinal permeability
dc.titleBcs class iv oral drugs and absorption windows: Regional-dependent intestinal permeability of furosemideen
dc.typearticle
dc.rights.licenseBY
dc.rights.license10.3390/pharmaceutics12121175
dcterms.abstractМарковић, Милица; Рагатскy, Инна; Зур, Моран; Цвијић, Сандра; Дахан, Aрик;
dc.citation.volume12
dc.citation.issue12
dc.citation.spage1
dc.citation.epage16
dc.citation.rankaM21~
dc.identifier.wos000602410100001
dc.identifier.doi10.3390/pharmaceutics12121175
dc.identifier.scopus2-s2.0-85097158533
dc.identifier.fulltexthttp://farfar.pharmacy.bg.ac.rs/bitstream/id/8487/BCS_Class_IV_pub_2020.pdf
dc.type.versionpublishedVersion


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