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Exploration of potential biomarkers for amoxicillin/clavulanate-induced liver injury in humans through multi-omics approaches
다중오믹스 분석법 기반 아목시실린/클라불란산 유발 인체 간손상 생체지표 탐색

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Authors
Jieon Lee
Advisor
조주연
Major
의과대학 협동과정임상약리학전공
Issue Date
2017-02
Publisher
서울대학교 대학원
Keywords
Drug-induced liver injurybiomarkerpharmacogenomicspharmacometabolomicsmicroRNAclinical trials
Description
학위논문 (박사)-- 서울대학교 대학원 : 협동과정임상약리학전공, 2017. 2. 조주연.
Abstract
Introduction: Drug-induced liver injury (DILI) is a major challenge in the development and use of therapeutic drugs. The exploration for more sensitive biomarkers of DILI requires multidirectional approaches. However, a comprehensive clinical study has not been conducted in healthy volunteers. To explore potential biomarkers for and mechanisms of amoxicillin/clavulanate-induced liver injury (AC-DILI), we conducted a clinical trial based on multi-omics approaches.
Methods: Thirty-two healthy Korean male volunteers were enrolled and grouped according to 4 GSTT1/M1 genotypes (8 subjects per group). Blood and urine samples were collected before and after 14 days of amoxicillin/clavulanic acid administration for liver function tests and quantification of biomarkers. The approaches used throughout this study included a liver function test, pharmacokinetic analysis, microRNA quantification, pharmacometabolomics analysis, human leukocyte antigen (HLA) typing, and lymphocyte transformation test (LTT). We evaluated the correlations between liver function parameters and multi-omics biomarkers.
Results: Comparative analyses between Responder and Non-Responder groups classified by the alanine aminotransferase (ALT) elevation level revealed no statistically significant differences in primary pharmacokinetic (PK) parameters of amoxicillin or clavulanate. Liver-specific microRNA-122 (miR-122) was highly correlated with ALT. Urinary metabolites, including 7-methylxanthine, 7-methyluric acid, 3-methylxanthine, and azelaic acid, showed significantly different levels between the two groups (P<0.05). Lymphocyte proliferation in response to the drug was also observed. These findings demonstrate sequential changes in the process of AC-DILI, including metabolic changes, increased miR-122 level, increased liver enzyme activity and enhanced lymphocyte proliferation after drug administration.
Conclusion: This is the first study to evaluate potential AC-DILI biomarkers in healthy volunteers. The results confirm miR-122 and four urinary metabolites as early and sensitive biomarkers for AC-DILI, suggesting hepatocellular injury, liver inflammation, and mitochondrial oxidative stress as mechanisms underlying AC-DILI. Proliferation of lymphocytes in response to the drug also suggests a role for the adaptive immune response in AC-DILI. The biomarkers evaluated in this study by integrating omics data could enable more sensitive and earlier prediction of liver injury in drug development and usage of therapeutics.
Language
English
URI
https://hdl.handle.net/10371/121793
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College of Medicine/School of Medicine (의과대학/대학원)Program in Clinical Pharmacology (협동과정-임상약리학전공)Theses (Ph.D. / Sc.D._협동과정-임상약리학전공)
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