Idiosyncratic Drug Induced Liver Injury, Cytochrome P450, Metabolic Risk Factors and Lipophilicity: Highlights and Controversies

Abstract

Progress in understanding the mechanisms of the idiosyncratic drug induced liver injury (iDILI) was highlighted in a scientometric investigation on the knowledge mapping of iDILI throughout the world, but uncertainty remained on metabolic risk factors of iDILI, the focus of the present review article. For the first time, a quantitative analysis of 3312 cases of iDILI assessed for causality with RUCAM (Roussel Uclaf Causality Assessment Method) showed that most drugs (61.1%) were metabolized by cytochrome P450 (CYP) isoforms: 49.6% by CYP 3A4/5, 24.6% by CYP 2C9, 13.2% by CYP 2E1, 7.3% by CYP 2C19, 3.5% by CYP 1A2 and 1.8% by CYP 2D6. Other studies showed high OR (odds ratio) for drugs metabolized by unspecified CYPs but the iDILI cases were not assessed for causality with RUCAM, a major shortcoming. In addition to critical comments on methodological flaws, several risk factors of iDILI were identified such as high but yet recommended daily drug doses, actual daily drug doses taken by the patients, hepatic drug metabolism and drug lipophilicity. These risk factors are subject to controversies by many experts seen critically also by others who outlined that none of these medication characteristics is able to predict iDILI with high confidence, leading to the statement of an outstanding caveat. It was also argued that all previous studies lacked comprehensive data because the number of examined drugs was relatively small as compared to the number of approved new molecular entities or currently used oral prescription drugs. In conclusion, trends are evident that some metabolic parameters are likely risk factors of iDILI but strong evidence can only be achieved when methodological issues will be successfully met.

Keywords: CYP isoforms; DILI; RUCAM; Roussel Uclaf Causality Assessment Method; cytochrome P450; daily drug dose; drug metabolism; iDILI; idiosyncratic drug induced liver injury; lipophilicity; metabolic risk factors; reactive oxygen species (ROS).

Figure 1

Metabolic pathways involved in liver injury caused by drugs. Potentially hepatotoxic drugs are commonly eliminated in the liver via metabolic pathways involving cytochrome P450 (CYP) isoforms of nonCYP dependent enzymes. Liver injury must be verified, before idiosyncratic drug induced liver injury (DILI) can be established as valid diagnosis requiring causality assessment with the updated RUCAM (Roussel Uclaf Causality Assessment Method) [8].