Active Eosinophilic Esophagitis Is Associated with Impaired Elimination of Budesonide by Cytochrome P450 3A Enzymes

Abstract

Background/Aims: Topically administered glucocorticoids such as budesonide have the potential of being established as first-line medical treatment of eosinophilic esophagitis (EoE). Safety of budesonide is based on high elimination by cytochrome P450 3A (CYP3A) enzymes. We aimed to investigate systemic absorption and elimination of a new budesonide formulation in patients with active EoE in comparison with healthy controls. Methods: After single and multiple doses of orodispersible budesonide (4 mg/day) the parent drug, its CYP3A-dependent metabolites, and endogenous cortisol were determined in 12 adult patients with active EoE and 12 healthy controls. An approved ileal-release formulation of budesonide was taken for reference. Molar ratios of metabolite formation in plasma were used as indices of CYP3A metabolic function. Results: CYP3A-dependent metabolite formation was significantly reduced in patients with active EoE as compared to healthy controls. Impaired biotransformation was reflected by a significantly higher extent of budesonide absorption and elongated elimination half-life in EoE patients. Comparison of morning serum cortisol levels at baseline with those after 1 week of treatment with budesonide revealed a significant decrease in EoE patients but not in healthy subjects. Conclusion: Active EoE is associated with reduced elimination of budesonide via CYP3A, the major subfamily of drug-metabolizing enzymes in humans.

A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis

“…Previously, it has been shown that only about 9% of budesonide from the effervescent tablet reaches the systemic circulation in patients with active EoE. 20 In contrast, oesophageal fungal infection (hyphae) occurred in some patients receiving budesonide. It is noteworthy that not all macroscopically suspected fungal infections were confirmed by the Grocott staining.…”

“…Recent studies of budesonide effervescent tablets used as mouthwash in patients with oral chronic graft versus host disease or as effervescent tablet for orodispersible use (BET) in patients with active EoE demonstrated a very low systemic bioavailability of budesonide. 19 20 …”

Advances in Clinical Management of Eosinophilic Esophagitis

“…Budesonide might have increased absorption from the gastrointestinal tract in patients with active inflammation, such as those with EoE. 136 Additionally, because grapefruit inhibits the CYP3A enzyme pathway responsible for the high first-pass effect of budesonide, patients taking this drug should not ingest grapefruit or its juice. 137 Oral candidiasis is uncommon, but esophageal candidiasis was identified in follow-up endoscopies of 15%-20% of patients treated with topical steroids.…”

Eosinophilic Esophagitis

“…113,114 It is reasonable to consider assessing the effects of both esophageal TCS and PPI on bone mineralization using bone density studies and to assess the absorption of esophageal TCS by checking cortisol levels. [115][116][117] With regard to elimination diets, nutritional guidance should be instituted to gauge whether there is adequate caloric intake and proper vitamin and mineral consumption. Because foods are being eliminated in a population that is allergic and has increased rates of anaphylaxis and food sensitization, the treating clinician should consider the possibility of loss of tolerance to food to which a subject is sensitized.…”