The American Journal of GASTROENTEROLOGY VOLUME 108 | AUGUST 2013 www.amjgastro.com ORIGINAL CONTRIBUTIONS nature publishing group 1344 COLON/SMALL BOWEL see related editorial on page x INTRODUCTION Celiac disease (CD) is a chronic autoimmune disorder of the small intestine that afects nearly 1% of most populations (1–3). In genetically susceptible individuals, inlammation is triggered by the ingestion of products containing cereals, such as wheat, rye, or barley, leading to crypt hyperplasia and villous atrophy in the small intestinal epithelium. As a consequence, a variety of gastrointestinal and extra-gastrointestinal symptoms develop. CYP3A4-Catalyzed Simvastatin Metabolism as a Non-Invasive Marker of Small Intestinal Health in Celiac Disease Belén Morón, PhD 1 , Anil K. Verma, MSc 2 , Prasenjit Das, MD 3 , Juha Taavela, BM 4,5 , Laila Dafik, PhD 6 , Thomas R. DiRaimondo, MS(ChemE) 7 , Megan A. Albertelli, DVM, PhD 8 , Thomas Kraemer, PhD 9 , Markku Mäki, MD, PhD 4,5 , Chaitan Khosla, PhD 6,7,10 , Gerhard Rogler, MD, PhD 1 and Govind K. Makharia, MD 2 OBJECTIVES: 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 ( C max ) of orally administered SV plus its major non-CYP3A4-derived metabolite SV acid (SV equivalent (SV eq )) 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 SV eq C max (46±24 nM) compared with treated patients (21±16 nM, P < 0.001) or healthy subjects (19±11 nM, P < 0.005). SV eq C max 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 SV eq C max showed a reduction in the value after 1 year of following a GFD. CONCLUSIONS: SV eq C max 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. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg Am J Gastroenterol 2013; 108:1344–1351; doi:10.1038/ajg.2013.151; published online 4 June 2013 1 Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland; 2 Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India; 3 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India; 4 Pediatric Research Center, School of Medicine, University of Tampere, Tampere, Finland; 5 Department of Pediatrics, Tampere University Hospital, Tampere, Finland; 6 Department of Biochemistry, Stanford University , Stanford, California, USA; 7 Department of Chemical Engineering, Stanford University , Stanford, California, USA; 8 Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California, USA; 9 Department of Forensic Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; 10 Department of Chemistry, Stanford University , Stanford, California, USA. Correspondence: Gerhard Rogler, MD, PhD, Division of Gastroenterology and Hepatology, University Hospital of Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. E-mail: Gerhard.Rogler@usz.ch Received 7 January 2013; accepted 15 April 2013