PT  - JOURNAL ARTICLE
AU  - Ke Yu
AU  - Xingchao Geng
AU  - Minjun Chen
AU  - Jie Zhang
AU  - Bingshun Wang
AU  - Katarina Ilic
AU  - Weida Tong
TI  - High Daily Dose and Being a Substrate of Cytochrome P450 Enzymes Are Two Important Predictors of Drug-Induced Liver Injury
AID  - 10.1124/dmd.113.056267
DP  - 2014 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 744--750
VI  - 42
IP  - 4
4099  - http://dmd.aspetjournals.org/content/42/4/744.short
4100  - http://dmd.aspetjournals.org/content/42/4/744.full
SO  - Drug Metab Dispos2014 Apr 01; 42
AB  - 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.