TY  - JOUR
AU  - Marković, Milica
AU  - Zur, Moran
AU  - Garsiani, Sapir
AU  - Porat, Daniel
AU  - Cvijić, Sandra
AU  - Amidon, Gordon L.
AU  - Dahan, Arik
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4194
AB  - The purpose of this study was to evaluate mechanisms behind the intestinal permeability of minoxidil, with special emphasis on paracellular transport, and elucidate the suitability of minoxidil to be a reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil (vs. metoprolol) was evaluated in-silico, in-vitro using both the PAMPA assay and across Caco-2 cell monolayers, as well as in-vivo in rats throughout the entire intestine. The permeability was studied in conditions that represent the different segments of the small intestine: upper jejunum (pH 6.5), mid small intestine (pH 7.0), distal ileum (pH 7.5), and colon (pH 6.5). Since we aimed to investigate the paracellular transport of minoxidil, we have also examined its permeability in the presence of quercetin (250 μM), which closes the tight junctions, and sodium decanoate (10 mM), which opens the tight junctions. While metoprolol demonstrated segmental-dependent rat and PAMPA permeability, with higher permeability in higher pH regions, the permeability of minoxidil was pH-independent. Minoxidil PAMPA permeability was significantly lower than its rat permeability, indicating a potential significant role of the paracellular route. In rat intestinal perfusion studies, and across Caco-2 monolayers, tight junction modifiers significantly affected minoxidil permeability; while the presence of quercetin caused decreased permeability, the presence of sodium decanoate caused an increase in minoxidil permeability. In accordance with these in-vitro and in-vivo results, in-silico simulations indicated that approximatelly 15% of minoxidil dose is absorbed paracellularly, mainly in the proximal parts of the intestine. The results of this study indicate that paracellular transport plays a significant role in the intestinal permeability of minoxidil following oral administration. Since this permeation route may lead to higher variability in comparison to transcellular, these findings diminish the suitability of minoxidil to serve as the low/high BSC permeability class benchmark.
PB  - MDPI
T2  - Pharmaceutics
T1  - The Role of Paracellular Transport in the Intestinal Absorption and Biopharmaceutical Characterization of Minoxidil
VL  - 14
IS  - 7
DO  - 10.3390/pharmaceutics14071360
ER  - 

@article{
author = "Marković, Milica and Zur, Moran and Garsiani, Sapir and Porat, Daniel and Cvijić, Sandra and Amidon, Gordon L. and Dahan, Arik",
year = "2022",
abstract = "The purpose of this study was to evaluate mechanisms behind the intestinal permeability of minoxidil, with special emphasis on paracellular transport, and elucidate the suitability of minoxidil to be a reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil (vs. metoprolol) was evaluated in-silico, in-vitro using both the PAMPA assay and across Caco-2 cell monolayers, as well as in-vivo in rats throughout the entire intestine. The permeability was studied in conditions that represent the different segments of the small intestine: upper jejunum (pH 6.5), mid small intestine (pH 7.0), distal ileum (pH 7.5), and colon (pH 6.5). Since we aimed to investigate the paracellular transport of minoxidil, we have also examined its permeability in the presence of quercetin (250 μM), which closes the tight junctions, and sodium decanoate (10 mM), which opens the tight junctions. While metoprolol demonstrated segmental-dependent rat and PAMPA permeability, with higher permeability in higher pH regions, the permeability of minoxidil was pH-independent. Minoxidil PAMPA permeability was significantly lower than its rat permeability, indicating a potential significant role of the paracellular route. In rat intestinal perfusion studies, and across Caco-2 monolayers, tight junction modifiers significantly affected minoxidil permeability; while the presence of quercetin caused decreased permeability, the presence of sodium decanoate caused an increase in minoxidil permeability. In accordance with these in-vitro and in-vivo results, in-silico simulations indicated that approximatelly 15% of minoxidil dose is absorbed paracellularly, mainly in the proximal parts of the intestine. The results of this study indicate that paracellular transport plays a significant role in the intestinal permeability of minoxidil following oral administration. Since this permeation route may lead to higher variability in comparison to transcellular, these findings diminish the suitability of minoxidil to serve as the low/high BSC permeability class benchmark.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "The Role of Paracellular Transport in the Intestinal Absorption and Biopharmaceutical Characterization of Minoxidil",
volume = "14",
number = "7",
doi = "10.3390/pharmaceutics14071360"
}

Marković, M., Zur, M., Garsiani, S., Porat, D., Cvijić, S., Amidon, G. L.,& Dahan, A.. (2022). The Role of Paracellular Transport in the Intestinal Absorption and Biopharmaceutical Characterization of Minoxidil. in Pharmaceutics
MDPI., 14(7).
https://doi.org/10.3390/pharmaceutics14071360

Marković M, Zur M, Garsiani S, Porat D, Cvijić S, Amidon GL, Dahan A. The Role of Paracellular Transport in the Intestinal Absorption and Biopharmaceutical Characterization of Minoxidil. in Pharmaceutics. 2022;14(7).
doi:10.3390/pharmaceutics14071360 .

Marković, Milica, Zur, Moran, Garsiani, Sapir, Porat, Daniel, Cvijić, Sandra, Amidon, Gordon L., Dahan, Arik, "The Role of Paracellular Transport in the Intestinal Absorption and Biopharmaceutical Characterization of Minoxidil" in Pharmaceutics, 14, no. 7 (2022),
https://doi.org/10.3390/pharmaceutics14071360 . .

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 . .

TY  - JOUR
AU  - Marković, Milica
AU  - Zur, Moran
AU  - Dahan, Arik
AU  - Cvijić, Sandra
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3635
AB  - In this study, we aimed to elucidate biopharmaceutical characteristics of the anti-ulcer drug rebamipide, with special emphasis on the influence of gastrointestinal (GI) mucus on rebamipide segmental-dependent permeability and absorption. Experimental studies and physiologically-based pharmacokinetic (GastroPlusTM) simulations were used to elucidate segmental-dependent absorption and pharmacokinetic (PK) profile, accounting for various drug properties, including solubility/dissolution limitations, regional-dependent drug affinity to mucus and membrane permeability, as well as physiological factors such as regional-pH differences along the intestine, thickness and types of mucus, transit time and surface areas. Low permeability and extensive binding to GI mucus were the key modeling features, and accounting for these resulted in good fitting between the predicted and in-vivo PK profiles, validating the ability of the model to pinpoint the underlying mechanisms of rebamipide limited oral bioavailability. Furthermore, the simulations indicated regional-dependent intestinal permeability of rebamipide, with absorption rank order of jejunum>ileum>duodenum>colon, mainly attributable to segmental mucus differences. Food effect simulations indicated somewhat decreased rebamipide absorption in the fed state, in corroboration with previous reports. Since this anti-ulcer drug is currently examined for additional indications, this work provides important input for future development of rebamipide.
PB  - Elsevier B.V.
T2  - European Journal of Pharmaceutical Sciences
T1  - Biopharmaceutical characterization of rebamipide: The role of mucus binding in regional-dependent intestinal permeability
VL  - 152
DO  - 10.1016/j.ejps.2020.105440
ER  - 

@article{
author = "Marković, Milica and Zur, Moran and Dahan, Arik and Cvijić, Sandra",
year = "2020",
abstract = "In this study, we aimed to elucidate biopharmaceutical characteristics of the anti-ulcer drug rebamipide, with special emphasis on the influence of gastrointestinal (GI) mucus on rebamipide segmental-dependent permeability and absorption. Experimental studies and physiologically-based pharmacokinetic (GastroPlusTM) simulations were used to elucidate segmental-dependent absorption and pharmacokinetic (PK) profile, accounting for various drug properties, including solubility/dissolution limitations, regional-dependent drug affinity to mucus and membrane permeability, as well as physiological factors such as regional-pH differences along the intestine, thickness and types of mucus, transit time and surface areas. Low permeability and extensive binding to GI mucus were the key modeling features, and accounting for these resulted in good fitting between the predicted and in-vivo PK profiles, validating the ability of the model to pinpoint the underlying mechanisms of rebamipide limited oral bioavailability. Furthermore, the simulations indicated regional-dependent intestinal permeability of rebamipide, with absorption rank order of jejunum>ileum>duodenum>colon, mainly attributable to segmental mucus differences. Food effect simulations indicated somewhat decreased rebamipide absorption in the fed state, in corroboration with previous reports. Since this anti-ulcer drug is currently examined for additional indications, this work provides important input for future development of rebamipide.",
publisher = "Elsevier B.V.",
journal = "European Journal of Pharmaceutical Sciences",
title = "Biopharmaceutical characterization of rebamipide: The role of mucus binding in regional-dependent intestinal permeability",
volume = "152",
doi = "10.1016/j.ejps.2020.105440"
}

Marković, M., Zur, M., Dahan, A.,& Cvijić, S.. (2020). Biopharmaceutical characterization of rebamipide: The role of mucus binding in regional-dependent intestinal permeability. in European Journal of Pharmaceutical Sciences
Elsevier B.V.., 152.
https://doi.org/10.1016/j.ejps.2020.105440

Marković M, Zur M, Dahan A, Cvijić S. Biopharmaceutical characterization of rebamipide: The role of mucus binding in regional-dependent intestinal permeability. in European Journal of Pharmaceutical Sciences. 2020;152.
doi:10.1016/j.ejps.2020.105440 .

Marković, Milica, Zur, Moran, Dahan, Arik, Cvijić, Sandra, "Biopharmaceutical characterization of rebamipide: The role of mucus binding in regional-dependent intestinal permeability" in European Journal of Pharmaceutical Sciences, 152 (2020),
https://doi.org/10.1016/j.ejps.2020.105440 . .