TY  - JOUR
AU  - Porat, Daniel
AU  - Dukhno, Oleg
AU  - Cvijić, Sandra
AU  - Dahan, Arik
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5393
AB  - Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is associated with higher body mass index (BMI). Sildenafil solubility was determined both in vitro and ex vivo, using pre- vs. postsurgery gastric contents aspirated from patients. Dissolution tests were done in conditions mimicking the stomach before surgery, after sleeve gastrectomy (post-SG, pH 5), and after one anastomosis gastric bypass (post-OAGB, pH 7). Finally, these data were included in physiologically based pharmacokinetic (PBPK) modelling (GastroPlus®) to simulate sildenafil PK before vs. after surgery. pH-dependent solubility was demonstrated with low solubility (0.3 mg/mL) at pH 7 vs. high solubility at pH 1–5, which was also confirmed ex vivo with much lower solubility values in postbariatric gastric samples. Hampered dissolution of all sildenafil doses was obtained under post-OAGB conditions compared with complete (100%) dissolution under both presurgery and post-SG conditions. PBPK simulations revealed delayed sildenafil absorption in postbariatric patients (increased tmax) and reduced Cmax, especially in post-OAGB patients, relative to a presurgery state. Hence, the effect of bariatric surgery on sildenafil PK is unpredictable and may depend on the specific bariatric procedure. This mechanistically based analysis suggests a potentially undesirable delayed onset of action of sildenafil following gastric bypass surgery.
PB  - MDPI
T2  - Pharmaceutics
T1  - The Complexity of Bariatric Patient’s Pharmacotherapy: Sildenafil Biopharmaceutics and Pharmacokinetics before vs. after Gastric Sleeve/Bypass
VL  - 15
IS  - 12
DO  - 10.3390/pharmaceutics15122795
ER  - 

@article{
author = "Porat, Daniel and Dukhno, Oleg and Cvijić, Sandra and Dahan, Arik",
year = "2023",
abstract = "Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is associated with higher body mass index (BMI). Sildenafil solubility was determined both in vitro and ex vivo, using pre- vs. postsurgery gastric contents aspirated from patients. Dissolution tests were done in conditions mimicking the stomach before surgery, after sleeve gastrectomy (post-SG, pH 5), and after one anastomosis gastric bypass (post-OAGB, pH 7). Finally, these data were included in physiologically based pharmacokinetic (PBPK) modelling (GastroPlus®) to simulate sildenafil PK before vs. after surgery. pH-dependent solubility was demonstrated with low solubility (0.3 mg/mL) at pH 7 vs. high solubility at pH 1–5, which was also confirmed ex vivo with much lower solubility values in postbariatric gastric samples. Hampered dissolution of all sildenafil doses was obtained under post-OAGB conditions compared with complete (100%) dissolution under both presurgery and post-SG conditions. PBPK simulations revealed delayed sildenafil absorption in postbariatric patients (increased tmax) and reduced Cmax, especially in post-OAGB patients, relative to a presurgery state. Hence, the effect of bariatric surgery on sildenafil PK is unpredictable and may depend on the specific bariatric procedure. This mechanistically based analysis suggests a potentially undesirable delayed onset of action of sildenafil following gastric bypass surgery.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "The Complexity of Bariatric Patient’s Pharmacotherapy: Sildenafil Biopharmaceutics and Pharmacokinetics before vs. after Gastric Sleeve/Bypass",
volume = "15",
number = "12",
doi = "10.3390/pharmaceutics15122795"
}

Porat, D., Dukhno, O., Cvijić, S.,& Dahan, A.. (2023). The Complexity of Bariatric Patient’s Pharmacotherapy: Sildenafil Biopharmaceutics and Pharmacokinetics before vs. after Gastric Sleeve/Bypass. in Pharmaceutics
MDPI., 15(12).
https://doi.org/10.3390/pharmaceutics15122795

Porat D, Dukhno O, Cvijić S, Dahan A. The Complexity of Bariatric Patient’s Pharmacotherapy: Sildenafil Biopharmaceutics and Pharmacokinetics before vs. after Gastric Sleeve/Bypass. in Pharmaceutics. 2023;15(12).
doi:10.3390/pharmaceutics15122795 .

Porat, Daniel, Dukhno, Oleg, Cvijić, Sandra, Dahan, Arik, "The Complexity of Bariatric Patient’s Pharmacotherapy: Sildenafil Biopharmaceutics and Pharmacokinetics before vs. after Gastric Sleeve/Bypass" in Pharmaceutics, 15, no. 12 (2023),
https://doi.org/10.3390/pharmaceutics15122795 . .

TY  - JOUR
AU  - Porat, Daniel
AU  - Dukhno, Oleg
AU  - Partook-Maccabi, Mazal
AU  - Vainer, Ella
AU  - Cvijić, Sandra
AU  - Dahan, Arik
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5038
AB  - Anatomical/physiological gastrointestinal changes after bariatric surgery may influence the fate of orally administered drugs. Since non-selective NSAIDs are not well-tolerated post-surgery, selective cyclooxygenase-2 (COX-2) inhibitors may be important for these patients. In this work we investigated celecoxib, etoricoxib and etodolac, for impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in-vitro, and ex-vivo in aspirated gastric contents from patients pre- vs. post-surgery. Dissolution was studied in conditions simulating pre- vs. post-surgery stomach. Finally, the experimental solubility data were used in physiologically-based biopharmaceutics model (PBBM) (GastroPlus®) to simulate pre- vs. post-surgery celecoxib/etoricoxib/etodolac pharmacokinetic (PK) profiles. For etoricoxib and etodolac (but not celecoxib), pH-dependent solubility was demonstrated: etoricoxib solubility decreased ∼1000-fold, and etodolac solubility increased 120-fold, as pH increased from 1 to 7, which was also confirmed ex-vivo. Hampered etoricoxib dissolution and improved etodolac dissolution post-surgery was revealed. Tablet crushing, clinically recommended after surgery, failed to improve post-bariatric dissolution. PBBM simulations revealed significantly impaired etoricoxib absorption post-surgery across all conditions; for instance, 79% lower Cmax and 53% decreased AUC was simulated post-gastric bypass procedure, after single 120 mg dose. Celecoxib and etodolac maintained unaffected absorption after bariatric surgery. This mechanistically-based analysis suggests to prefer the acidic drug etodolac or the neutral celecoxib as selective COX-2 inhibitors, over the basic drug etoricoxib, after bariatric surgery.
PB  - Elsevier B.V.
T2  - International Journal of Pharmaceutics
T1  - Selective COX-2 inhibitors after bariatric surgery: Celecoxib, etoricoxib and etodolac post-bariatric solubility/dissolution and pharmacokinetics
VL  - 645
DO  - 10.1016/j.ijpharm.2023.123347
ER  - 

@article{
author = "Porat, Daniel and Dukhno, Oleg and Partook-Maccabi, Mazal and Vainer, Ella and Cvijić, Sandra and Dahan, Arik",
year = "2023",
abstract = "Anatomical/physiological gastrointestinal changes after bariatric surgery may influence the fate of orally administered drugs. Since non-selective NSAIDs are not well-tolerated post-surgery, selective cyclooxygenase-2 (COX-2) inhibitors may be important for these patients. In this work we investigated celecoxib, etoricoxib and etodolac, for impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in-vitro, and ex-vivo in aspirated gastric contents from patients pre- vs. post-surgery. Dissolution was studied in conditions simulating pre- vs. post-surgery stomach. Finally, the experimental solubility data were used in physiologically-based biopharmaceutics model (PBBM) (GastroPlus®) to simulate pre- vs. post-surgery celecoxib/etoricoxib/etodolac pharmacokinetic (PK) profiles. For etoricoxib and etodolac (but not celecoxib), pH-dependent solubility was demonstrated: etoricoxib solubility decreased ∼1000-fold, and etodolac solubility increased 120-fold, as pH increased from 1 to 7, which was also confirmed ex-vivo. Hampered etoricoxib dissolution and improved etodolac dissolution post-surgery was revealed. Tablet crushing, clinically recommended after surgery, failed to improve post-bariatric dissolution. PBBM simulations revealed significantly impaired etoricoxib absorption post-surgery across all conditions; for instance, 79% lower Cmax and 53% decreased AUC was simulated post-gastric bypass procedure, after single 120 mg dose. Celecoxib and etodolac maintained unaffected absorption after bariatric surgery. This mechanistically-based analysis suggests to prefer the acidic drug etodolac or the neutral celecoxib as selective COX-2 inhibitors, over the basic drug etoricoxib, after bariatric surgery.",
publisher = "Elsevier B.V.",
journal = "International Journal of Pharmaceutics",
title = "Selective COX-2 inhibitors after bariatric surgery: Celecoxib, etoricoxib and etodolac post-bariatric solubility/dissolution and pharmacokinetics",
volume = "645",
doi = "10.1016/j.ijpharm.2023.123347"
}

Porat, D., Dukhno, O., Partook-Maccabi, M., Vainer, E., Cvijić, S.,& Dahan, A.. (2023). Selective COX-2 inhibitors after bariatric surgery: Celecoxib, etoricoxib and etodolac post-bariatric solubility/dissolution and pharmacokinetics. in International Journal of Pharmaceutics
Elsevier B.V.., 645.
https://doi.org/10.1016/j.ijpharm.2023.123347

Porat D, Dukhno O, Partook-Maccabi M, Vainer E, Cvijić S, Dahan A. Selective COX-2 inhibitors after bariatric surgery: Celecoxib, etoricoxib and etodolac post-bariatric solubility/dissolution and pharmacokinetics. in International Journal of Pharmaceutics. 2023;645.
doi:10.1016/j.ijpharm.2023.123347 .

Porat, Daniel, Dukhno, Oleg, Partook-Maccabi, Mazal, Vainer, Ella, Cvijić, Sandra, Dahan, Arik, "Selective COX-2 inhibitors after bariatric surgery: Celecoxib, etoricoxib and etodolac post-bariatric solubility/dissolution and pharmacokinetics" in International Journal of Pharmaceutics, 645 (2023),
https://doi.org/10.1016/j.ijpharm.2023.123347 . .

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  - Porat, Daniel
AU  - Dukhno, Oleg
AU  - Vainer, Ella
AU  - Cvijić, Sandra
AU  - Dahan, Arik
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4241
AB  - Gastrointestinal anatomical/physiological changes after bariatric surgery influence variables affecting the fate of drugs after ingestion, and medication management of these patients requires a thorough and complex mechanistic analysis. The aim of this research was to study whether loratadine/desloratadine antiallergic treatment of bariatric patients is at risk of being ineffective due to impaired solubility/dissolution. The pH-depend- ent solubility of loratadine/desloratadine was studied in vitro, as well as ex vivo, in gastric content aspirated from patients before versus after bariatric surgery. Then, a biorelevant dissolution method was developed to simulate the gastric conditions after sleeve gastrectomy (SG) or one-anastomosis gastric bypass (OAGB), accounting for key variables (intragastric volume, pH, and contractility), and the dissolution of loratadine/desloratadine was studied pre- versus post-surgery. Dissolution was also studied after tablet crushing or syrup ingestion, as these actions are recommended after bariatric surgery. Finally, these experimental data were implemented in a newly developed physiologically based pharmacokinetic (PBPK) model to simulate loratadine/desloratadine PK profiles pre- versus post-surgery. For both drugs, pH-dependent solubility was demonstrated, with decreased solubility at higher pH; over the pH range 1−7, loratadine solubility decreased ∼2000-fold, and desloratadine decreased ∼120-fold. Ex vivo solubility in aspirated human gastric fluid pre- versus post-surgery was in good agreement with these in vitro results and revealed that while desloratadine solubility still allows complete dissolution post-surgery, loratadine solubility post-surgery is much lower than the threshold required for the complete dissolution of the drug dose. Indeed, severely hampered loratadine dissolution was revealed, dropping from 100% pre-surgery to only 3 and 1% post-SG and post-OAGB, respectively. Tablet crushing did not increase loratadine dissolution in any post-bariatric condition, nor did loratadine syrup in post-OAGB (pH 7) media, while in post-laparoscopic SG conditions (pH 5), the syrup provided partial improvement of up to 40% dissolution. Desloratadine exhibited quick and complete dissolution across all pre-/post-surgery conditions. PBPK simulations revealed pronounced impaired absorption of loratadine post- surgery, with 84−88% decreased Cmax, 28−36% decreased Fa, and 24−31% decreased overall bioavailability, depending on the type of bariatric procedure. Desloratadine absorption remained unchanged post-surgery. We propose that desloratadine should be preferred over loratadine in bariatric patients, and as loratadine is an over-the-counter medication, antiallergic therapy after bariatric surgery requires special attention by patients and clinicians alike. This mechanistic approach that reveals potential post-surgery complexity, and at the same time provides adequate substitutions, may contribute to better pharmacotherapy and overall patient care after bariatric surgery.
PB  - American Chemical Society
T2  - Molecular Pharmaceutics
T1  - Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery
VL  - 19
IS  - 8
SP  - 2922
EP  - 2936
DO  - 10.1021/acs.molpharmaceut.2c00292
ER  - 

@article{
author = "Porat, Daniel and Dukhno, Oleg and Vainer, Ella and Cvijić, Sandra and Dahan, Arik",
year = "2022",
abstract = "Gastrointestinal anatomical/physiological changes after bariatric surgery influence variables affecting the fate of drugs after ingestion, and medication management of these patients requires a thorough and complex mechanistic analysis. The aim of this research was to study whether loratadine/desloratadine antiallergic treatment of bariatric patients is at risk of being ineffective due to impaired solubility/dissolution. The pH-depend- ent solubility of loratadine/desloratadine was studied in vitro, as well as ex vivo, in gastric content aspirated from patients before versus after bariatric surgery. Then, a biorelevant dissolution method was developed to simulate the gastric conditions after sleeve gastrectomy (SG) or one-anastomosis gastric bypass (OAGB), accounting for key variables (intragastric volume, pH, and contractility), and the dissolution of loratadine/desloratadine was studied pre- versus post-surgery. Dissolution was also studied after tablet crushing or syrup ingestion, as these actions are recommended after bariatric surgery. Finally, these experimental data were implemented in a newly developed physiologically based pharmacokinetic (PBPK) model to simulate loratadine/desloratadine PK profiles pre- versus post-surgery. For both drugs, pH-dependent solubility was demonstrated, with decreased solubility at higher pH; over the pH range 1−7, loratadine solubility decreased ∼2000-fold, and desloratadine decreased ∼120-fold. Ex vivo solubility in aspirated human gastric fluid pre- versus post-surgery was in good agreement with these in vitro results and revealed that while desloratadine solubility still allows complete dissolution post-surgery, loratadine solubility post-surgery is much lower than the threshold required for the complete dissolution of the drug dose. Indeed, severely hampered loratadine dissolution was revealed, dropping from 100% pre-surgery to only 3 and 1% post-SG and post-OAGB, respectively. Tablet crushing did not increase loratadine dissolution in any post-bariatric condition, nor did loratadine syrup in post-OAGB (pH 7) media, while in post-laparoscopic SG conditions (pH 5), the syrup provided partial improvement of up to 40% dissolution. Desloratadine exhibited quick and complete dissolution across all pre-/post-surgery conditions. PBPK simulations revealed pronounced impaired absorption of loratadine post- surgery, with 84−88% decreased Cmax, 28−36% decreased Fa, and 24−31% decreased overall bioavailability, depending on the type of bariatric procedure. Desloratadine absorption remained unchanged post-surgery. We propose that desloratadine should be preferred over loratadine in bariatric patients, and as loratadine is an over-the-counter medication, antiallergic therapy after bariatric surgery requires special attention by patients and clinicians alike. This mechanistic approach that reveals potential post-surgery complexity, and at the same time provides adequate substitutions, may contribute to better pharmacotherapy and overall patient care after bariatric surgery.",
publisher = "American Chemical Society",
journal = "Molecular Pharmaceutics",
title = "Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery",
volume = "19",
number = "8",
pages = "2922-2936",
doi = "10.1021/acs.molpharmaceut.2c00292"
}

Porat, D., Dukhno, O., Vainer, E., Cvijić, S.,& Dahan, A.. (2022). Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery. in Molecular Pharmaceutics
American Chemical Society., 19(8), 2922-2936.
https://doi.org/10.1021/acs.molpharmaceut.2c00292

Porat D, Dukhno O, Vainer E, Cvijić S, Dahan A. Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery. in Molecular Pharmaceutics. 2022;19(8):2922-2936.
doi:10.1021/acs.molpharmaceut.2c00292 .

Porat, Daniel, Dukhno, Oleg, Vainer, Ella, Cvijić, Sandra, Dahan, Arik, "Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery" in Molecular Pharmaceutics, 19, no. 8 (2022):2922-2936,
https://doi.org/10.1021/acs.molpharmaceut.2c00292 . .

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 . .