High daily dose and being a substrate of cytochrome P450 enzymes are two important predictors of drug-induced liver injury.
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.
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.).
Ke
K
Yu
Xingchao
X
Geng
Minjun
M
Chen
Jie
J
Zhang
Bingshun
B
Wang
Katarina
K
Ilic
Weida
W
Tong
D000284:Administration, Oral; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000378:metabolism*; D003580:Cytochromes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016015:Logistic Models; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism*; D011237:Predictive Value of Tests; D013379:Substrate Specificity
D003580:Cytochromes; D004364:Pharmaceutical Preparations; C013464:cytochrome P420