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Bcs class iv oral drugs and absorption windows: Regional-dependent intestinal permeability of furosemide

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2020
BCS_Class_IV_pub_2020.pdf (2.383Mb)
Authors
Marković, Milica
Zur, Moran
Ragatsky, Inna
Cvijić, Sandra
Dahan, Arik
Article (Published version)
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Abstract
Biopharmaceutical 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.

Keywords:
Biopharmaceutics / BCS class IV drugs / Furosemide / Intestinal absorption / Oral drug delivery / Physiologically-based pharmacokinetic (PBPK) modeling / Segmental-dependent intestinal permeability
Source:
Pharmaceutics, 2020, 12, 12, 1-16
Publisher:
  • MDPI AG

DOI: 10.3390/pharmaceutics12121175

ISSN: 1999-4923

WoS: 000602410100001

Scopus: 2-s2.0-85097158533
[ Google Scholar ]
16
7
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/3753
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
TY  - JOUR
AU  - Marković, Milica
AU  - Zur, Moran
AU  - Ragatsky, Inna
AU  - Cvijić, Sandra
AU  - Dahan, Arik
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3753
AB  - Biopharmaceutical 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.
PB  - MDPI AG
T2  - Pharmaceutics
T1  - Bcs class iv oral drugs and absorption windows: Regional-dependent intestinal permeability of furosemide
VL  - 12
IS  - 12
SP  - 1
EP  - 16
DO  - 10.3390/pharmaceutics12121175
ER  - 
@article{
author = "Marković, Milica and Zur, Moran and Ragatsky, Inna and Cvijić, Sandra and Dahan, Arik",
year = "2020",
abstract = "Biopharmaceutical 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.",
publisher = "MDPI AG",
journal = "Pharmaceutics",
title = "Bcs class iv oral drugs and absorption windows: Regional-dependent intestinal permeability of furosemide",
volume = "12",
number = "12",
pages = "1-16",
doi = "10.3390/pharmaceutics12121175"
}
Marković, M., Zur, M., Ragatsky, I., Cvijić, S.,& Dahan, A.. (2020). Bcs class iv oral drugs and absorption windows: Regional-dependent intestinal permeability of furosemide. in Pharmaceutics
MDPI AG., 12(12), 1-16.
https://doi.org/10.3390/pharmaceutics12121175
Marković M, Zur M, Ragatsky I, Cvijić S, Dahan A. Bcs class iv oral drugs and absorption windows: Regional-dependent intestinal permeability of furosemide. in Pharmaceutics. 2020;12(12):1-16.
doi:10.3390/pharmaceutics12121175 .
Marković, Milica, Zur, Moran, Ragatsky, Inna, Cvijić, Sandra, Dahan, Arik, "Bcs class iv oral drugs and absorption windows: Regional-dependent intestinal permeability of furosemide" in Pharmaceutics, 12, no. 12 (2020):1-16,
https://doi.org/10.3390/pharmaceutics12121175 . .

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