Literature DB >> 18094037

Induction of metabolism and transport in human intestine: validation of precision-cut slices as a tool to study induction of drug metabolism in human intestine in vitro.

Esther G van de Kerkhof1, Inge A M de Graaf, Anna-Lena B Ungell, Geny M M Groothuis.   

Abstract

Induction of drug enzyme activity in the intestine can strongly determine plasma levels of drugs. It is therefore important to predict drug-drug interactions in human intestine in vitro. We evaluated the applicability of human intestinal precision-cut slices for induction studies in vitro. Morphological examination and intracellular ATP levels indicated tissue integrity up to 24 h of incubation, whereas in proximal jejunum slices, the metabolic rate toward most substrates remained at 40 to 50% of initial values. In colon slices, the cytochrome P450 conversions were below the detection limit, but conjugation rates remained relatively constant during incubation. The inducibility of drug-metabolizing enzymes and P-glycoprotein was evaluated using prototypical inducers for five induction pathways. beta-Naphthoflavone (aryl hydrocarbon receptor ligand) induced CYP1A1 (132-fold in colon and 362-fold in proximal jejunum) and UDP glucuronosyltransferase (UGT) 1A6 mRNA (9.8-fold in colon and 3.2-fold in proximal jejunum). In proximal jejunum, rifampicin (RIF) [pregnane X receptor (PXR) ligand] induced CYP3A4 (5.2-fold), CYP2B6 (2-fold), UGT1A6 (2.2-fold), and multidrug resistance-1 (MDR1)/ABCB1 mRNA (2.7-fold), whereas 6beta-hydroxytestosterone formation (CYP3A4) increased 2-fold. In colon, RIF induced UGT1A6 32-fold and MDR1 2.2-fold. Dexamethasone (glucocorticoid receptor and PXR ligand) induced CYP3A4 mRNA (3.5-fold) and activity (5-fold) in proximal jejunum. Phenobarbital (constitutive androstane receptor activator) induced CYP3A4 (4.1-fold, only in jejunum), CYP2B6 (4.9-fold in colon and 2.3-fold in proximal jejunum), and MDR1/ABCB1 mRNA and CYP3A4 activity (2-fold only proximal jejunum). Quercetin (nuclear factor-E2-related factor 2 activator) induced UGT1A6 mRNA (6.7-fold in colon and 2.2-fold in proximal jejunum). In conclusion, this study shows that human intestinal precision-cut slices are useful to study induction of drug-metabolizing enzymes and transporters in the human intestine.

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Year:  2007        PMID: 18094037     DOI: 10.1124/dmd.107.018820

Source DB:  PubMed          Journal:  Drug Metab Dispos        ISSN: 0090-9556            Impact factor:   3.922


  12 in total

1.  Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies.

Authors:  Inge A M de Graaf; Peter Olinga; Marina H de Jager; Marjolijn T Merema; Ruben de Kanter; Esther G van de Kerkhof; Geny M M Groothuis
Journal:  Nat Protoc       Date:  2010-08-19       Impact factor: 13.491

2.  Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics.

Authors:  E D Kharasch; D Whittington; D Ensign; C Hoffer; P S Bedynek; S Campbell; K Stubbert; A Crafford; A London; T Kim
Journal:  Clin Pharmacol Ther       Date:  2012-03-07       Impact factor: 6.875

Review 3.  Role of CAR and PXR in xenobiotic sensing and metabolism.

Authors:  Yue-Ming Wang; Su Sien Ong; Sergio C Chai; Taosheng Chen
Journal:  Expert Opin Drug Metab Toxicol       Date:  2012-05-03       Impact factor: 4.481

4.  Piperine activates human pregnane X receptor to induce the expression of cytochrome P450 3A4 and multidrug resistance protein 1.

Authors:  Yue-Ming Wang; Wenwei Lin; Sergio C Chai; Jing Wu; Su Sien Ong; Erin G Schuetz; Taosheng Chen
Journal:  Toxicol Appl Pharmacol       Date:  2013-05-22       Impact factor: 4.219

5.  Human cytochrome P450 1A1 structure and utility in understanding drug and xenobiotic metabolism.

Authors:  Agnes A Walsh; Grazyna D Szklarz; Emily E Scott
Journal:  J Biol Chem       Date:  2013-03-18       Impact factor: 5.157

Review 6.  Gutsy science: In vitro systems of the human intestine to model oral drug disposition.

Authors:  Christopher M Arian; Tomoki Imaoka; Jade Yang; Edward J Kelly; Kenneth E Thummel
Journal:  Pharmacol Ther       Date:  2021-08-31       Impact factor: 12.310

7.  Precision-cut rat, mouse, and human intestinal slices as novel models for the early-onset of intestinal fibrosis.

Authors:  Bao Tung Pham; Wouter Tobias van Haaften; Dorenda Oosterhuis; Judith Nieken; Inge Anne Maria de Graaf; Peter Olinga
Journal:  Physiol Rep       Date:  2015-04

8.  Duodenum Intestine-Chip for preclinical drug assessment in a human relevant model.

Authors:  Magdalena Kasendra; Raymond Luc; Jianyi Yin; Dimitris V Manatakis; Gauri Kulkarni; Carolina Lucchesi; Josiah Sliz; Athanasia Apostolou; Laxmi Sunuwar; Jenifer Obrigewitch; Kyung-Jin Jang; Geraldine A Hamilton; Mark Donowitz; Katia Karalis
Journal:  Elife       Date:  2020-01-14       Impact factor: 8.140

9.  Inhibitory effects of quercetin and its major metabolite quercetin-3-O-β-D-glucoside on human UDP-glucuronosyltransferase 1A isoforms by liquid chromatography-tandem mass spectrometry.

Authors:  Rui Zhang; Ye Wei; Tingyu Yang; Xixi Huang; Jinping Zhou; Chunxiao Yang; Jiani Zhou; Yani Liu; Shaojun Shi
Journal:  Exp Ther Med       Date:  2021-06-06       Impact factor: 2.447

10.  Rifampicin Induces Gene, Protein, and Activity of P-Glycoprotein (ABCB1) in Human Precision-Cut Intestinal Slices.

Authors:  Ondrej Martinec; Carin Biel; Inge A M de Graaf; Martin Huliciak; Koert P de Jong; Frantisek Staud; Filip Cecka; Peter Olinga; Ivan Vokral; Lukas Cerveny
Journal:  Front Pharmacol       Date:  2021-06-09       Impact factor: 5.810

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