S-Space College of Medicine/School of Medicine (의과대학/대학원) Program in Clinical Pharmacology (협동과정-임상약리학전공) Theses (Ph.D. / Sc.D._협동과정-임상약리학전공)
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
- Jieon Lee
- 의과대학 협동과정임상약리학전공
- Issue Date
- 서울대학교 대학원
- Drug-induced liver injury; biomarker; pharmacogenomics; pharmacometabolomics; microRNA; clinical trials
- 학위논문 (박사)-- 서울대학교 대학원 : 협동과정임상약리학전공, 2017. 2. 조주연.
- 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.