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High Daily Dose and Being a Substrate of Cytochrome P450 Enzymes Are Two Important Predictors of Drug-Induced Liver Injury

Yu, Ke, Geng, Xingchao, Chen, Minjun, Zhang, Jie, Wang, Bingshun, Ilic, Katarina, Tong, Weida·2014·Drug Metabolism and Disposition
DOI 10.1124/dmd.113.056267
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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.

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  • Concomitant drugs can modulate the metabolism of other drugs through induction, inhibition, or substrate competition, particularly the CYP450 reaction, thus affecting the individual risk of iDILI.

    “Concomitant drugs can modulate the metabolism of other drugs through induction, inhibition, or substrate competition, and particularly the CYP 450 reaction, thus affecting the individual risk of iDILI [35].”

    From Chinese guideline for the diagnosis and treatment of drug-induced liver injury: an update (2024) · cites this paper as [35]

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Metadata

Authors
Yu, K., Geng, X., Chen, M., Zhang, J., Wang, B., Ilic, K., & Tong, W.
Venue
Drug Metabolism and Disposition
Publisher
Elsevier BV
Published
2014-04
Volume
42
Issue
4
Pages
744-750
ISSN
0090-9556
DOI
10.1124/dmd.113.056267
Cited by
150
References
0
Language
en
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