Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery

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-dependent 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 C max, 28–36% decreased F a, 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.

Impact of Obesity and Bariatric Surgery on Metabolic Enzymes and P-glycoprotein Activity using Geneva Cocktail Approach

“…Omeprazole MR was somewhat higher (12.1%) in patients, yet this difference did not achieve statistical significance. When the AUC of the parent drug was investigated, they not only did not decrease after surgery (as would be projected due to the reduction of the absorption site); however, they also increased substantially in patients who experienced bypass surgery (because the pH is higher in this type of surgery rather than sleeve surgery [40]). These findings are probably attributable to the elevated AUC of enteric-coated omeprazole granules at the new pH.…”

The Complexity of Bariatric Patient’s Pharmacotherapy: Sildenafil Biopharmaceutics and Pharmacokinetics before vs. after Gastric Sleeve/Bypass

“…The study protocol was approved by the institutional review board of the Ben-Gurion University School of Medicine (institutional board request number 0248-18-SOR) and informed consent was obtained presurgery from all patients. pH measurements and recording were done immediately after gastric content collection; the content was vortexed, and 2 mL of gastric fluid were centrifuged for 10 min at 20,817× g and 25 °C; 400 µL of supernatant fluid was used in the solubility experiment [ 20 , 21 ]. Samples with appropriate pH [ 16 ] and sufficient gastric fluid volume were chosen for the solubility study.…”

“…To account for postbariatric surgery changes in physiological conditions, the ACAT model parameters were manually adjusted, i.e., gastric volume was decreased from default 50 to 10 mL, corresponding to 20% of the presurgery gastric volume [ 35 , 36 ], and gastric transit time was decreased from default 0.25 to 0.12 h [ 37 , 38 ]. The simulations were also performed for bypassed duodenum and jejunum physiology in post-OAGB patients, setting the volume, length, and transit time for the duodenum and jejunum 1 and 2 segments to zero [ 20 , 36 ]. Moreover, stomach pH was increased from default pH 1.3 to pH 5.0 (post-SG) and pH 7.0 (post-OAGB) to account for the influence of the different bariatric procedures and gastric pH on drug dissolution and absorption [ 16 , 39 ].…”

“…These changes may severely hamper the dissolution of the drug dose, a prerequisite for drug absorption [ 18 , 19 ]. Some drugs, including those with limited water solubility, high dose, and a weakly basic nature, are more prone and may be more sensitive to these postbariatric changes than others [ 20 , 21 ].…”

Can Consultation by a Clinical Pharmacist Prevent Morbidity and Mortality in Patients Undergoing Bariatric Surgery?

“…In addition, bariatric surgery is accompanied by anatomical changes that may affect the pharmacokinetic profile and the pharmacodynamics of many drugs. These changes include, among others, a decrease in stomach acidity [14], a decrease in the stomach volume, and bypass of the proximal part of the intestine and thus a decrease in surface area for absorption, and various enzymes and transporters that take part in drug metabolism and distribution [15][16][17]. Also, many changes may be required in the patient's chronic medication dosing due to an improvement in chronic diseases such as diabetes, hypertension, and hyperlipidemia.…”