In:
BMJ Open, BMJ, Vol. 10, No. 3 ( 2020-03), p. e034086-
Abstract:
Severity of coeliac disease depends in part on the extent of small intestinal mucosa injury. Patients with the most abnormal pathology have loss of duodenal villi CYP3A4, a drug-metabolising enzyme that inactivates many drugs. These patients are hypothesised to have greater systemic concentrations of felodipine, a drug which normally has low oral bioavailability secondary to intestinal CYP3A4-mediated metabolism. It serves as a representative for a class containing many medications. Design A phase I, open-label, single-dose, pharmacokinetic study. Setting London, Ontario, Canada. Participants Patients with coeliac disease (n=47) with positive serology and healthy individuals (n=68). Main outcome measures Patients with coeliac disease—upper gastrointestinal endoscopy and oral felodipine pharmacokinetics study within a 3-week period. Healthy individuals—oral felodipine pharmacokinetics study with water and grapefruit juice. Results Coeliac stratification categories: Group A (n=15, normal), B+C (n=16, intraepithelial lymphocytosis with/without mild villous blunting) and D (n=16, moderate/severe villous blunting). Groups A, B+C and D had linear trends of increasing felodipine AUC 0–8 ; mean±SEM, 14.4±2.1, 17.6±2.8, 25.7±5.0; p 〈 0.05) and Cmax (3.5±0.5, 4.0±0.6, 6.4±1.1; p 〈 0.02), respectively. Healthy subjects receiving water had lower felodipine AUC 0 – 8 (11.9±0.9 vs 26.9±0.9, p=0.0001) and Cmax (2.9±0.2 vs 7.7±0.2, p=0.0001) relative to those receiving grapefruit juice. Conclusions Increased felodipine concentrations in patients with coeliac disease were most probably secondary to decreased small intestinal CYP3A4 expression. Patients with severe coeliac disease and healthy individuals with grapefruit juice had equivalently enhanced effect. Thus, patients with severe coeliac disease would probably experience similarly altered drug response, including overdose toxicity, from many important medications known to be metabolised by CYP3A4. Patients with coeliac disease with severe disease should be considered for other clinical drug management, particularly when there is the potential for serious drug toxicity.
Type of Medium:
Online Resource
ISSN:
2044-6055
,
2044-6055
DOI:
10.1136/bmjopen-2019-034086
Language:
English
Publisher:
BMJ
Publication Date:
2020
detail.hit.zdb_id:
2599832-8
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