title: (1)H-Nuclear magnetic resonance-based metabolic profiling of nonsteroidal anti-inflammatory drug-induced adverse effects in rats.
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs), which are globally prescribed, exhibit mainly anti-inflammatory and analgesic effects but also can cause adverse effects including gastrointestinal erosions, ulceration, bleeding, and perforation. The purpose of this study was to investigate surrogate biomarkers associated with the gastrointestinal (GI) damage caused by NSAID treatment using pattern recognition analysis of (1)H-nuclear magnetic resonance ((1)H NMR) spectra of rat urine. Urine was collected for 5h after oral administration of the following NSAIDs at low or high doses: acetylsalicylic acid (10 or 200mgkg(-1)), diclofenac (0.5 or 15mgkg(-1)), piroxicam (1 or 10mgkg(-1)), indomethacin (1 or 25mgkg(-1)), or ibuprofen (10, or 150mgkg(-1)) as nonselective COX inhibitors and celecoxib (10 or 100mgkg(-1)) as a COX-2 selective inhibitor. The urine was analyzed using 500MHz (1)H NMR for spectral binning and targeted profiling and the level of gastric damage was examined. The nonselective COX inhibitors caused severe gastric damage while no lesions were observed in the celecoxib-treated rats. The (1)H NMR urine spectra were divided into spectral bins (0.04ppm) for global profiling, and a total of 44 endogenous metabolites were assigned for targeted profiling. Multivariate data analyses were performed to recognize the spectral pattern of endogenous metabolites related to NSAIDs using partial least square-discrimination analysis (PLS-DA). The (1)H NMR spectra clustered differently according to gastric damage score in global profiling. In targeted profiling, the endogenous metabolites of citrate, allantoin, 2-oxoglutarate, acetate, benzoate, glycine, and trimethylamine N-oxide were selected as putative biomarkers for gastric damage caused by NSAIDs. These putative biomarkers might be useful for predicting the risk of adverse effects caused by NSAIDs in the early stage of drug development process.
authors: Seoul Regional Food & Drug Administration, Ministry of Food and Drug Safety, 212, Mokdongjungang-ro, Yangcheon-gu, Seoul, Republic of Korea; Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, Republic of Korea.
authors: So Young
authors: SY
authors: Um
authors: Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, Republic of Korea.
authors: Jung Hyun
authors: JH
authors: Park
authors: Pharmaceutical and Medical Devices Research Department, Ministry of Food and Drug Safety, Osong Health Technology Administration Complex, 643 Yeonje-ri, Gangoe-myeon, Cheongwon-gun, Chungcheongbuk-do, Republic of Korea.
authors: Myeon Woo
authors: MW
authors: Chung
authors: Pharmaceutical and Medical Devices Research Department, Ministry of Food and Drug Safety, Osong Health Technology Administration Complex, 643 Yeonje-ri, Gangoe-myeon, Cheongwon-gun, Chungcheongbuk-do, Republic of Korea.
authors: Ki Hwan
authors: KH
authors: Choi
authors: Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, Republic of Korea. Electronic address: hwalee@ewha.ac.kr.
authors: Hwa Jeong
authors: HJ
authors: Lee
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001241:Aspirin / Q000009:adverse effects; D000068579:Celecoxib / Q000009:adverse effects; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects; D004008:Diclofenac / Q000009:adverse effects; D064420:Drug-Related Side Effects and Adverse Reactions / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D007052:Ibuprofen / Q000009:adverse effects; D007213:Indomethacin / Q000009:adverse effects; D016018:Least-Squares Analysis; D008279:Magnetic Resonance Imaging / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D055432:Metabolomics / Q000379:methods; D010894:Piroxicam / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D010894:Piroxicam; D004008:Diclofenac; D000068579:Celecoxib; D001241:Aspirin; D007052:Ibuprofen; D007213:Indomethacin
keywords: (1)H-Nuclear magnetic resonance; Biomarker; Gastrointestinal damage; Metabolomics; Nonsteroidal anti-inflammatory drugs; Partial least square-discrimination analysis