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ENTERIC CYP3A4 EXPRESSION AND ACTIVITY AS A FUNCTION OF DUODENAL INFLAMMATION IN PATIENTS WITH CELIAC DISEASE
G Dresser, U Schwarz, R Kim, D Bailey, D Driman, J Parfitt, T Ponich, N Chande, J Gregor
University of Western Ontario, London, Ontario
Aims: The aim of this study is to correlate the expression and activity of enteric CYP3A4 with the degree of duodenal inflammation in adults with celiac disease.
Methods: Male or female patients, 18-75 years, with positive celiac serology, a previous diagnosis of celiac disease, and/or symptoms compatible with celiac disease were enrolled. Elective, diagnostic upper endoscopic biopsies and serology were performed. In order to determine activity of enteric CYP3A4, patients with active (positive biopsy for atrophied villi) or with inactive (positive serology only) celiac disease were invited to complete a pharmacokinetic study using the CYP3A4 probe drug felodipine within 3 weeks of endoscopy. Plasma concentrations of felodipine and metabolite were quantified just before and at specific times after drug administration. Duodenal biopsy samples were prepared for mRNA, protein, and immunohistochemical analysis. Severity of histological changes were graded using a modification of the Marsh classification. Expression of mRNA was determined for CYP3A4, IL-6, and TNFalpha using RT-PCR. Semiquantitative western blotting for CYP3A4 was performed.
Results: CYP3A4 content normalized to villin as determined by Western blotting varied over 100-fold. Compared to patients with normal duodenal histology, those with severe villous atrophy had significantly decreased CYP3A4 protein expression, while felodipine bioavailability (AUC) and maximum concentrations (Cmax) were increased by 52% and 85%, respectively. Degree of histologic change on biopsy did not correlate with rate of formation of felodipine metabolite. Felodipine AUC and Cmax did not correlate with CYP3A4 content by Western blot. Assessment of mRNA from duodenal samples is ongoing and will be reported.
Conclusions: Compared to celiac disease patients with normal duodenal histology, those with active celiac disease and villous atrophy have reduced CYP3A4 expression and activity, resulting in higher plasma concentrations of the prototypical CYP3A4 substrate felodipine. Enteric CYP3A4 metabolism appears to be more important than absorptive surface area as a determinant of felodipine absorption in patients with celiac disease.