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.
Highlights
Idiosyncratic drug induced liver injury was the focus of three recent publications dealing with specific issues [1,2,3]
More challenging are studies in humans because the liver is known as a secret keeping organ, hardly accessible [5] and, more importantly, patients with Idiosyncratic drug induced liver injury (iDILI) evaluated by a robust causality assessment method (CAM) such as Roussel Uclaf Causality Assessment Method (RUCAM) are rarely available as a homogenous study cohort in one place
Proposed risk factors like recommended daily drug doses, used daily drug doses, hepatic drug metabolism and drug lipophilicity are certainly insufficient due to major methodological problems leading to serious caveats
Summary
Idiosyncratic drug induced liver injury (iDILI) was the focus of three recent publications dealing with specific issues [1,2,3]. Among the top 10 drugs were amoxicillin-clavulanate, flucloxacillin, atorvastatin, disulfiram, diclofenac, simvastatin, carbamazepine, ibuprofen, erythromycin and anabolic steroids as body building agents This ranking would likely reflect the extent of the drug use and probably not the strength of their hepatotoxicity. The idiosyncratic nature of the liver injury means that the liver injury is specific to a patient and is unpredictable, rare and not reproducible in animal models [4] These characteristics make it difficult to establish risk factors based on pathogenetic principles, that would add to problems extrapolating animal results to human disease [4,5]. More challenging are studies in humans because the liver is known as a secret keeping organ, hardly accessible [5] and, more importantly, patients with iDILI evaluated by a robust causality assessment method (CAM) such as RUCAM are rarely available as a homogenous study cohort in one place. A broad range of drugs are potentially hepatotoxic and may lead to variable clinical features
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