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Hepatology 2013 Jul;58(1):388-96

High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury.

Chen M, Borlak J, Tong W


Drug induced liver injury (DILI) is a leading cause of drug failure in clinical trials and a major reason for drug withdrawals from the market. While there is evidence for doses of >/= 100mg/day to be associated with increased risk for hepatotoxicity, many drugs are safe at such doses. There is unmet need to predict more reliably risk for DILI and lipophilicity might be a contributing factor. We analyzed the combined factors of daily dose and lipophilicity for 164 FDA-approved oral medications and observed high risk for hepatotoxicity (odds ratio: 14.05, P < 0.001) for drugs given at daily doses >/= 100mg and logP >/= 3. This defined the "rule-of-two". Similar results were obtained for an independent set of 179 oral medications with 85% of the "rule-of-two" positives being associated with hepatotoxicity (odds ratio: 3.89, P < 0.01). Using the WHO Anatomical Therapeutic Chemical classification system, the "rule-of-two" performed best in predicting DILI in seven therapeutic categories. Among 15 "rule-of-two" positives, 14 were withdrawn hepatotoxic drugs and one was OTC medication labeled for liver injury. We additionally examined drug pairs that have similar chemical structures and act on the same molecular target but differ in their potential for DILI. Again, the "rule-of-two" predicted reliable hepatotoxicity. Finally, the "rule-of-two" was applied to clinical case studies to identify hepatotoxic drugs in complex co-medication regimes to further demonstrate its utility. Conclusion: Apart from dose, lipophilicity contributes significantly to risk for hepatotoxicity. Applying the "rule-of-two" is an appropriate means to estimate risk for DILI as compared to dose alone. (HEPATOLOGY 2012.).

Category: Journal Article
PubMed ID: #23258593 DOI: 10.1002/hep.26208
Includes FDA Authors from Scientific Area(s): Toxicological Research
Entry Created: 2012-12-22 Entry Last Modified: 2014-02-22