title: CYP3A4-catalyzed simvastatin metabolism as a non-invasive marker of small intestinal health in celiac disease.
abstract: OBJECTIVE
  Histological examination of duodenal biopsies is the gold standard for assessing intestinal damage in celiac disease (CD). A noninvasive marker of disease status is necessary, because obtaining duodenal biopsies is invasive and not suitable for routine monitoring of CD patients. As the small intestine is a major site of cytochrome P450 3A4 (CYP3A4) activity and also the location of the celiac lesion, we investigated whether patients with active CD display abnormal pharmacokinetics of an orally administered CYP3A4 substrate, simvastatin (SV), which could potentially be used for noninvasive assessment of their small intestinal health.
  
  
  METHODS
  Preclinical experiments were performed in CYP3A4-humanized mice to examine the feasibility of the test. Subsequently, a clinical trial was undertaken with 11 healthy volunteers, 18 newly diagnosed patients with CD, and 25 celiac patients who had followed a gluten-free diet (GFD) for more than 1 year. The maximum concentration (Cmax) of orally administered SV plus its major non-CYP3A4-derived metabolite SV acid (SV equivalent (SVeq)) was measured, and compared with clinical, histological, and serological parameters.
  
  
  RESULTS
  In CYP3A4-humanized mice, a marked decrease in SV metabolism was observed in response to enteropathy. In the clinical setting, untreated celiac patients displayed a significantly higher SVeq Cmax (46±24 nM) compared with treated patients (21±16 nM, P<0.001) or healthy subjects (19±11 nM, P<0.005). SVeq Cmax correctly predicted the diagnosis in 16/18 untreated celiac patients, and also the recovery status of all follow-up patients that exhibited normal or near-normal biopsies (Marsh 0-2). All patients with abnormal SVeq Cmax showed a reduction in the value after 1 year of following a GFD.
  
  
  CONCLUSIONS
  SVeq Cmax is a promising noninvasive marker for assessment of small intestinal health. Further studies are warranted to establish its clinical utility for assessing gut status of patients with CD.
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Belén
authors.initials: B
authors.lastname: Morón
authors.forename: Anil K
authors.initials: AK
authors.lastname: Verma
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Das
authors.forename: Juha
authors.initials: J
authors.lastname: Taavela
authors.forename: Laila
authors.initials: L
authors.lastname: Dafik
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Diraimondo
authors.forename: Megan A
authors.initials: MA
authors.lastname: Albertelli
authors.forename: Thomas
authors.initials: T
authors.lastname: Kraemer
authors.forename: Markku
authors.initials: M
authors.lastname: Mäki
authors.forename: Chaitan
authors.initials: C
authors.lastname: Khosla
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
authors.forename: Govind K
authors.initials: GK
authors.lastname: Makharia
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002446:Celiac Disease / Q000188:drug therapy* / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D055050:Diet, Gluten-Free; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D007150:Immunohistochemistry; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D012372:ROC Curve; D019821:Simvastatin / Q000493:pharmacokinetics*
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human