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CYP3A4-Catalyzed Simvastatin Metabolism as a Non-Invasive Marker of Small Intestinal Health in Celiac Disease

Morón, Belén PhD1; Verma, Anil K MSc2; Das, Prasenjit MD3; Taavela, Juha BM4, 5; Dafik, Laila PhD6; DiRaimondo, Thomas R MS(ChemE)7; Albertelli, Megan A DVM, PhD8; Kraemer, Thomas PhD9; Mäki, Markku MD, PhD4, 5; Khosla, Chaitan PhD6, 7, 10; Rogler, Gerhard MD, PhD1; Makharia, Govind K MD2

American Journal of Gastroenterology: August 2013 - Volume 108 - Issue 8 - p 1344–1351
doi: 10.1038/ajg.2013.151
Colon/Small Bowel
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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 (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 SVeqCmax (46±24 nM) compared with treated patients (21±16 nM,P<0.001) or healthy subjects (19±11 nM,P<0.005). SVeqCmax 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 SVeqCmax showed a reduction in the value after 1 year of following a GFD.

CONCLUSIONS: SVeqCmax 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.

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

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/A787

Received 7 January 2013; accepted 15 April 2013

published online 4 June 2013

© The American College of Gastroenterology 2013. All Rights Reserved.
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