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Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery
dc.creator | Porat, Daniel | |
dc.creator | Dukhno, Oleg | |
dc.creator | Vainer, Ella | |
dc.creator | Cvijić, Sandra | |
dc.creator | Dahan, Arik | |
dc.date.accessioned | 2022-08-02T10:14:54Z | |
dc.date.available | 2022-08-02T10:14:54Z | |
dc.date.issued | 2022 | |
dc.identifier.issn | 1543-8384 | |
dc.identifier.uri | https://farfar.pharmacy.bg.ac.rs/handle/123456789/4241 | |
dc.description.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. | |
dc.publisher | American Chemical Society | |
dc.relation | info:eu-repo/grantAgreement/MESTD/inst-2020/200161/RS// | |
dc.rights | restrictedAccess | |
dc.source | Molecular Pharmaceutics | |
dc.subject | aspirated gastric content | |
dc.subject | bariatric surgery | |
dc.subject | biorelevant dissolution | |
dc.subject | drug solubility | |
dc.subject | oral absorption | |
dc.subject | physiologically based PK simulations | |
dc.subject | stomach pH | |
dc.subject | weak bases | |
dc.title | Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery | |
dc.type | article | |
dc.rights.license | ARR | |
dc.citation.volume | 19 | |
dc.citation.issue | 8 | |
dc.citation.spage | 2922 | |
dc.citation.epage | 2936 | |
dc.citation.rank | M21 | |
dc.identifier.wos | 00082191030000 | |
dc.identifier.doi | 10.1021/acs.molpharmaceut.2c00292 | |
dc.identifier.scopus | 2-s2.0-85134835155 | |
dc.type.version | publishedVersion |