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  - 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 . .