Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas (K.Y., M.C., J.Z., W.T.); National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, China's State Food and Drug Administration, Beijing, China (X.G.); Department of Biostatistics, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.W.); and Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (K.I.).
Drug Metab Dispos. 2014 Apr;42(4):744-50. doi: 10.1124/dmd.113.056267. Epub 2014 Jan 24.
Drug-induced liver injury (DILI) is complicated and difficult to predict. It has been observed that drugs with extensive hepatic metabolism have a higher likelihood of causing DILI. Cytochrome P450 (P450) enzymes are primarily involved in hepatic metabolism. Identifying the associations of DILI with drugs that are P450 substrates, inhibitors, or inducers will be extremely helpful to clinicians during the decision-making process of caring for a patient suspected of having DILI. We collected metabolism data on P450 enzymes for 254 orally administered drugs in the Liver Toxicity Knowledge Base Benchmark Dataset with a known daily dose, and applied logistic regression to identify these associations. We revealed that drugs that are substrates of P450 enzymes have a higher likelihood of causing DILI [odds ratio (OR), 3.99; 95% confidence interval (95% CI), 2.07-7.67; P < 0.0001], which is dose-independent, and drugs that are P450 inhibitors have a higher likelihood of generating DILI only when they are administered at high daily doses (OR, 6.03; 95% CI, 1.32-27.5; P = 0.0098). However, drugs that are P450 inducers are not observed to be associated with DILI (OR, 1.55; 95% CI, 0.65-3.68; P = 0.3246). Our findings will be useful in identifying the suspected medication as a cause of liver injury in clinical settings.
药物性肝损伤（DILI）复杂且难以预测。人们观察到，具有广泛肝代谢的药物更有可能引起 DILI。细胞色素 P450（P450）酶主要参与肝代谢。鉴定 DILI 与 P450 底物、抑制剂或诱导剂药物的关联，将在临床医生对疑似 DILI 患者进行治疗决策时提供极大帮助。我们从具有已知日剂量的 Liver Toxicity Knowledge Base Benchmark Dataset 中收集了 254 种口服药物的 P450 酶代谢数据，并应用逻辑回归来识别这些关联。我们发现，P450 酶底物药物更有可能引起 DILI [比值比（OR），3.99；95%置信区间（95% CI），2.07-7.67；P < 0.0001]，这种关联与剂量无关，而 P450 抑制剂只有在高日剂量给药时才更有可能产生 DILI（OR，6.03；95% CI，1.32-27.5；P = 0.0098）。然而，P450 诱导剂药物与 DILI 无关（OR，1.55；95% CI，0.65-3.68；P = 0.3246）。我们的发现将有助于在临床环境中识别疑似导致肝损伤的药物。
