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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Article number123347
JournalInternational Journal of Pharmaceutics
Volume645
DOIs
StatePublished - 15 Oct 2023

Keywords

  • Bariatric surgery
  • Biorelevant dissolution
  • Drug solubility
  • Oral absorption
  • Physiologically-based pharmacokinetic (PBPK) simulations
  • Stomach pH

ASJC Scopus subject areas

  • Pharmaceutical Science

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