Utility of human cytochrome P450 inhibition data in the assessment of drug-induced liver injury

Abstract

1. Drug-induced liver injury (DILI) is a major cause of drug development discontinuation and drug withdrawal from the market, but there are no golden standard methods for DILI risk evaluation. Since we had found the association between DILI and CYP1A1 or CYP1B1 inhibition, we further evaluated the utility of cytochrome P450 (P450) inhibition assay data for DILI risk evaluation using decision tree analysis.

2. The inhibitory activity of drugs with DILI concern (DILI drugs) and no DILI concern (no-DILI drugs) against 10 human P450s was assessed using recombinant enzymes and luminescent substrates. The drugs were also subjected to cytotoxicity assays and high-content analysis using HepG2 cells. Molecular descriptors were calculated by alvaDesc.

3. Decision tree analysis was performed with the data obtained as variables with or without P450-inhibitory activity to discriminate between DILI drugs and no-DILI drugs. The accuracy was significantly higher when P450-inhibitory activity was included. After the decision tree discrimination, the drugs were further discriminated with the P450-inhibitory activity. The results demonstrated that many false-positive and false-negative drugs were correctly discriminated by using the P450 inhibition data.

4. These results suggest that P450 inhibition assay data are useful for DILI risk evaluation.

Keywords:

• cytochrome P450 inhibition
• drug-induced liver injury
• in vitro assay
• decision tree
• molecular descriptor

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Acknowledgment

This study was conducted in part in collaboration with Daiichi Sankyo Company, Limited. The authors would like to thank Dr. Yuki Shimizu, Ms. Eri Yonekawa, Mr. Hirokazu Yamazaki, Ms. Rui Ogura, Dr. Michiko Watanabe, Ms. Chie Nakayama, and Ms. Midori Akaike (University of Shizuoka) for performing in vitro assays.

Disclosure statement

The authors declare no conflict of interest other than Daiichi Sankyo Company, Limited.

Data availability statement

Data are available upon reasonable request.

Funding

This study was financially supported in part by Daiichi Sankyo Company, Limited.