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Severity of coeliac disease and clinical management study when using a CYP3A4 metabolised medication: a phase I
Marc L Chretien1, David G Bailey2,3, Linda Asher1
1Medicine, London Health Sciences Centre, London, Ontario, Canada.
Objective:
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 AUC0-8; 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 AUC0-8 (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.
Insights
Coeliac disease patients show higher felodipine levels due to reduced intestinal CYP3A4 enzyme activity. Severe coeliac disease increases drug toxicity risk, similar to grapefruit juice interactions.
Area of Science:
- Pharmacology and Gastroenterology
- Drug Metabolism and Pharmacokinetics
Background:
- Coeliac disease involves small intestinal injury, potentially affecting drug metabolism.
- Cytochrome P450 3A4 (CYP3A4) is a key enzyme in drug inactivation, with reduced activity in coeliac disease patients.
- Felodipine's bioavailability is limited by CYP3A4 metabolism, making it a suitable model drug.
Purpose of the Study:
- To investigate the pharmacokinetic differences of felodipine in coeliac disease patients compared to healthy individuals.
- To assess the impact of coeliac disease severity on drug metabolism and systemic drug concentrations.
Main Methods:
- A Phase I, open-label, single-dose pharmacokinetic study was conducted.
- Participants included 47 coeliac disease patients (stratified by severity) and 68 healthy controls.
- Oral felodipine pharmacokinetics were measured in coeliac patients and in healthy individuals with and without grapefruit juice.
Main Results:
- Felodipine area under the curve (AUC) and Cmax increased with coeliac disease severity (Groups A, B+C, D).
- Healthy subjects consuming grapefruit juice showed significantly higher felodipine AUC and Cmax compared to those consuming water.
- A linear trend of increasing felodipine AUC and Cmax was observed with increasing severity of coeliac disease.
Conclusions:
- Reduced small intestinal CYP3A4 expression likely increases felodipine concentrations in coeliac disease patients.
- Severe coeliac disease poses a risk of altered drug response and toxicity, comparable to grapefruit juice interactions.
- Coeliac disease patients with severe pathology require careful clinical drug management, especially for CYP3A4-metabolized drugs.
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