Department of Biomedical Engineering, University of North Carolina at Chapel Hill, North Carolina, USA.
Clin Pharmacol Ther. 2010 Jul;88(1):45-51. doi: 10.1038/clpt.2009.240. Epub 2010 Feb 24.
Achieving the ability to identify individuals who are susceptible to drug-induced liver injury (DILI) would represent a major advance in personalized medicine. Clayton et al. demonstrated that the pattern of endogenous metabolites in urine could predict susceptibility to acetaminophen-induced liver injury in rats. We designed a clinical study to test this approach in healthy adults who received 4 g of acetaminophen per day for 7 days. Urine metabolite profiles obtained before the start of treatment were not sufficient to distinguish which of the subjects would develop mild liver injury, as indicated by a rise in alanine aminotransferase (ALT) to a level more than twice the baseline value (responders). However, profiles obtained shortly after the start of treatment, but prior to ALT elevation, could distinguish responders from nonresponders. Statistical analyses revealed that predictive metabolites included those derived from the toxic metabolite N-acetyl paraquinone imine (NAPQI), but that the inclusion of endogenous metabolites was required for significant prediction. This "early-intervention pharmaco-metabonomics" approach should now be tested in clinical trials of other potentially hepatotoxic drugs.
实现识别易发生药物性肝损伤 (DILI) 的个体的能力将代表个性化医疗的重大进展。Clayton 等人证明，尿液中内源性代谢物的模式可以预测大鼠对乙酰氨基酚诱导的肝损伤的易感性。我们设计了一项临床研究，以测试该方法在每天接受 4 克对乙酰氨基酚治疗 7 天的健康成年人中的效果。在开始治疗之前获得的尿代谢物谱不足以区分哪些受试者会发生丙氨酸氨基转移酶 (ALT) 升高超过基线值两倍以上的轻度肝损伤（应答者）。然而，在开始治疗后不久但在 ALT 升高之前获得的谱可以区分应答者和无应答者。统计分析表明，预测代谢物包括来自有毒代谢物 N-乙酰对苯醌亚胺 (NAPQI) 的代谢物，但需要包括内源性代谢物才能进行显著预测。这种“早期干预药物代谢组学”方法现在应该在其他潜在肝毒性药物的临床试验中进行测试。
