Drug interaction with UDP-Glucuronosyltransferase (UGT) enzymes is a predictor of drug-induced liver injury

Abstract

Background and aims: DILI frequently contributes to the attrition of new drug candidates and is a common cause for the withdrawal of approved drugs from the market. Although some noncytochrome P450 (non-CYP) metabolism enzymes have been implicated in DILI development, their association with DILI outcomes has not been systematically evaluated.

Approach and results: In this study, we analyzed a large data set comprising 317 drugs and their interactions in vitro with 42 non-CYP enzymes as substrates, inducers, and/or inhibitors retrieved from historical regulatory documents using multivariate logistic regression. We examined how these in vitro drug-enzyme interactions are correlated with the drugs' potential for DILI concern, as classified in the Liver Toxicity Knowledge Base database. Our study revealed that drugs that inhibit non-CYP enzymes are significantly associated with high DILI concern. Particularly, interaction with UDP-glucuronosyltransferases (UGT) enzymes is an important predictor of DILI outcomes. Further analysis indicated that only pure UGT inhibitors and dual substrate inhibitors, but not pure UGT substrates, are significantly associated with high DILI concern.

Conclusions: Drug interactions with UGT enzymes may independently predict DILI, and their combined use with the rule-of-two model further improves overall predictive performance. These findings could expand the currently available tools for assessing the potential for DILI in humans.

Graphical abstract

FIGURE 1

Stacked bar plot showing drug interaction with UGT applied as a predictor of DILI concern to 7 main anatomical/pharmacological groups (group size > 20) of the World Health Organization ATC classification system. The balanced accuracy of the predictor is shown as a line graph against the secondary y-axis, with the dotted teal line showing 50% balanced accuracy. ATC code: A, alimentary tract and metabolism; C, cardiovascular system; G, genito urinary system and sex hormones; J, anti-infectives for systemic use; L, antineoplastic and immunomodulating agents; M, musculo-skeletal system; N, nervous system. Abbreviations: ATC, anatomical therapeutic chemical; UGT, UDP-glucuronosyltransferases.