CYP3A4 Activity is Markedly Lower in Patients with Crohn’s Disease.

CYP3A4 Activity is Markedly Lower in Patients with Crohn’s Disease.

Inflamm Bowel Dis. 2017 Mar 15;:

Authors: Wilson A, Tirona RG, Kim RB

Abstract
BACKGROUND: Disease-dependent changes in the activity of drug metabolizing enzymes and transporters, such as Cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), are thought to have a major influence on the disposition of shared substrates. However, little is known regarding the in vivo relevance of these 2 proteins during drug therapy for gastrointestinal diseases. Our aim was to elucidate the activity of CYP3A4 and P-gp in subjects with Crohn’s disease (CD) and to evaluate their influence on budesonide pharmacokinetics.
METHODS: A detailed pharmacokinetic assessment was conducted in 8 individuals diagnosed with CD on stable doses of oral budesonide, a putative shared CYP3A4, and P-gp substrate, where hepatic and intestinal CYP3A4 activity were also assessed using intravenous and oral midazolam. In addition, oral fexofenadine was used as an in vivo probe for P-gp activity.
RESULTS: Budesonide area under the curve was highly variable between subjects but similar to previously reported values in healthy subjects. The hepatic and intestinal extraction ratios for midazolam were 0.11 ± 0.06 and 0.64 ± 0.25, respectively; however, CYP3A4 activity was nearly 5-fold lower in our CD cohort compared with published data among healthy subjects. Multivariate regression revealed that only 25% budesonide clearance could be explained based on midazolam or fexofenadine clearance.
CONCLUSIONS: Midazolam and fexofenadine disposition profile did not predict budesonide clearance. However, we observed a marked reduction in vivo CYP3A4 activity among individuals with CD. Therefore, changes in CYP3A4 activity in disease states such as CD may be a heretofore underappreciated determinant of variation in drug responsiveness in CD.

PMID: 28301431 [PubMed – as supplied by publisher]

PubMed Link: https://www.ncbi.nlm.nih.gov/pubmed/28301431?dopt=Abstract