Selective COX-2 inhibitors after bariatric surgery: Celecoxib, etoricoxib and etodolac post-bariatric solubility/dissolution and pharmacokinetics

Porat, Daniel; Dukhno, Oleg; Partook-Maccabi, Mazal; Vainer, Ella; Cvijić, Sandra; Dahan, Arik

doi:10.1016/j.ijpharm.2023.123347

Cited by 6 publications

(2 citation statements)

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“…Bariatric surgery may prolong the absorption half life, especially in bypass procedures. For many orally administered drugs, absorption occurs from the upper part of the small intestine [ 54 , 55 ], and, when bypassed, the full drug dose may only be absorbed later, as distally as the large intestine [ 20 , 56 ]. It should be highlighted that, particularly with sildenafil, the onset of action is desired to be as immediate as possible, and, hence, altered/delayed absorption (with lower C max and longer T max ) following gastric bypass is detrimental to treatment success, even with an unaffected AUC.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies predicted hampered dissolution, resulting in decreased blood levels for weakly basic drugs with particularly low pKa. These drugs were lamotrigine [ 21 ] (pKa = 5.7), loratadine [ 20 ] (pKa = 4.5), and etoricoxib (pKa = 4.6) [ 56 ]. Here, we showed that a basic drug with pKa in the upper limit of the physiological range (pKa ~6.7) is also sensitive to increased intragastric pH after bariatric surgery, suggesting that multiple other drugs with similar pKa values may also have altered dissolution and absorption following these procedures.…”

Section: Discussionmentioning

confidence: 99%

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

Porat,

Dukhno,

Cvijić

et al. 2023

Pharmaceutics

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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.

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