title: A comprehensive study of the association between drug hepatotoxicity and daily dose, liver metabolism, and lipophilicity using 975 oral medications.
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.
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Zuquan
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Kejian
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory Medicine, Nantong Maternal and Child Health Hospital, Nantong, Jiangsu, 226018, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shi
mesh_terms: D000284:Administration, Oral; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D008099:Liver / Q000187:drug effects*; D055553:Prescription Drugs / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D055553:Prescription Drugs
keywords: Pathology Section; dose; hepatotoxicity; lipophilicity; metabolism; oral