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 . .