Oncotarget

Research Papers: Pathology:

A comprehensive study of the association between drug hepatotoxicity and daily dose, liver metabolism, and lipophilicity using 975 oral medications

Zuquan Weng, Kejian Wang, Haibo Li and Qiang Shi _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:17031-17038. https://doi.org/10.18632/oncotarget.4400

Metrics: PDF 1165 views  |   HTML 1575 views  |   ?  


Abstract

Zuquan Weng1,*, Kejian Wang1,*, Haibo Li2, Qiang Shi1

1Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079, USA

2Department of Clinical Laboratory Medicine, Nantong Maternal and Child Health Hospital, Nantong, Jiangsu, 226018, China

*These authors have contributed equally to this work

Correspondence to:

Qiang Shi, e-mail: qiang.shi@fda.hhs.gov

Keywords: Pathology Section, hepatotoxicity, metabolism, lipophilicity, dose, oral

Received: June 05, 2015     Accepted: June 13, 2015     Published: June 24, 2015

ABSTRACT

It was recently suggested that daily dose, liver metabolism and lipophilicity were associated with an oral drug's potential to cause hepatotoxicity, but this has not been widely accepted. A likely reason is that published data lack comprehensiveness, as they were based on only about one third of all FDA approved single-active-ingredient oral prescription drugs. Here the 975 oral drugs used worldwide which have a Defined Daily Dose (DDD) designated in the World Health Organization's Anatomical Therapeutic Chemical classification system and whose hADRs potential and metabolism data are available in the Micromedex Drugdex® compendium were studied, with their lipophilicity calculated by the partition coefficient LogP. Of the 975 drugs examined, 49% (478) have the potential to induce at least one type of hepatic adverse drug reactions (hADRs) such as fatal hepatotoxicity, acute liver failure, significant ALT/AST elevation, hepatitis, and jaundice. By single factor analysis, a higher DDD (≥100 mg) was found to be associated with all types of hADRs, and extensive liver metabolism (≥50%) was associated with a subset of hADRs including fatal hADRs, hepatitis and jaundice, while LogP showed no relation to any types of hADRs. Contrary to previous reports, none of the combination, neither DDD and liver metabolism, nor DDD and LogP, was found to be more predictive of hADRs than using DDD or liver metabolism alone. These data provide convincing evidence that a higher daily dose and extensive liver metabolism, but not lipophilicity, are independent but not synergistic risk factors for oral drugs to induce hepatotoxicity.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 4400