title: CYP3A4 Activity is Markedly Lower in Patients with Crohn's Disease.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: *Division of Clinical Pharmacology, Department of Medicine, Western University, London, ON, Canada;†Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada; and‡Department of Physiology & Pharmacology, Western University, London, ON, Canada.
authors.forename: Aze
authors.initials: A
authors.lastname: Wilson
authors.forename: Rommel G
authors.initials: RG
authors.lastname: Tirona
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016022:Case-Control Studies; D003424:Crohn Disease / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000378:metabolism*; D008875:Middle Aged; D011379:Prognosis; D013379:Substrate Specificity; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016593:Terfenadine; C093230:fexofenadine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam