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.

The hydrogel patches with embedded microcapsules could achieve ultrasound responsive and enhanced transdermal delivery of diclofenac sodium.

The tyrosine kinase inhibitor regorafenib was approved by regulatory agencies for cancer treatment, albeit with strong warnings of severe hepatotoxicity included in the product label. The basis of this toxicity is unknown; one possible mechanism, that of mitochondrial damage, was tested. In isolated rat liver mitochondria, regorafenib directly uncoupled oxidative phosphorylation (OXPHOS) and promoted calcium overload-induced swelling, which were respectively prevented by the recoupler 6-ketocholestanol (KC) and the mitochondrial permeability transition (MPT) pore blocker cyclosporine A (CsA). In primary hepatocytes, regorafenib uncoupled OXPHOS, disrupted mitochondrial inner membrane potential (MMP), and decreased cellular ATP at 1h, and triggered MPT at 3h, which was followed by necrosis but not apoptosis at 7h and 24h, all of which were abrogated by KC. The combination of the glycolysis enhancer fructose plus the mitochondrial ATPase synthase inhibitor oligomycin A abolished regorafenib induced necrosis at 7h. This effect was not seen at 24h nor with the fructose or oligomycin A separately. CsA in combination with trifluoperazine, both MPT blockers, showed similar effects. Two compensatory mechanisms, activation of AMP-activated protein kinase (AMPK) to ameliorate ATP shortage and induction of autophagy to remove dysfunctional mitochondria, were found to be mobilized. Hepatocyte necrosis was enhanced either by the AMPK inhibitor Compound C or the autophagy inhibitor chloroquine, while autophagy inducer rapamycin was strongly cytoprotective. Remarkably, all toxic effects were observed at clinically-relevant concentrations of 2.5-15μM. These data suggest that uncoupling of OXPHOS and the resulting ATP shortage and MPT induction are the key mechanisms for regorafenib induced hepatocyte injury, and AMPK activation and autophagy induction serve as pro-survival pathways against such toxicity.

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