Abstract
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.
Footnotes
- Received December 2, 2013.
- Accepted January 23, 2014.
K.Y. is supported by the Research Participation Program at the National Center for Toxicological Research (NCTR) administrated by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration (FDA). B.W. is supported by the FDA/NCTR Division of Bioinformatics and Biostatistics, ORISE, Chinese Ministry of Science and Technology [National Science and Technology Mega Project Grant 2012ZX09301001-006(003)], and Shanghai Jiao Tong University [K.C. Wong Medical Fellowship Fund]. K.I. worked at NCTR during her summer sabbatical and was supported by ORISE and the Republic of Serbia Ministry of Education and Science (Project 175064, 2011–2014). The views presented in this article do not reflect those of the FDA. Any mention of commercial products is for clarification and is not intended to constitute endorsement or recommendation for use.
K.Y. and X.G. contributed equally to this work.
This article has supplemental material available at dmd.aspetjournals.org.
- U.S. Government work not protected by U.S. copyright
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