Novel strategies for the treatment of acetaminophen hepatotoxicity

Abstract

Introduction: Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Despite extensive investigations into the mechanisms of cell death, only a single antidote, N-acetylcysteine, is in clinical use. However, there have recently been more efforts made to translate mechanistic insight into identification of therapeutic targets and potential new drugs for this indication.Areas covered: After a short review of the key events in the pathophysiology of APAP-induced liver injury and recovery, the pros and cons of targeting individual steps in the pathophysiology as therapeutic targets are discussed. While the re-purposed drug fomepizole (4-methylpyrazole) and the new entity calmangafodipir are most advanced based on the understanding of their mechanism of action, several herbal medicine extracts and their individual components are also considered.Expert opinion: Fomepizole (4-methylpyrazole) is safe and has shown efficacy in preclinical models, human hepatocytes and in volunteers against APAP overdose. The safety of calmangafodipir in APAP overdose patients was shown but it lacks solid preclinical efficacy studies. Both drugs require a controlled phase III trial to achieve regulatory approval. All studies of herbal medicine extracts and components suffer from poor experimental design, which questions their clinical utility at this point.

Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity

“…Nevertheless, the present data show that the period of increased blood BA in humans may last for at least 100 hours after APAP overdose. Thus, the time-window when pharmacological interruption of futile BA cycling seems to be indicated exceeds the approximately 8 hours after intoxication during which the well-established therapy with N-acetylcysteine is efficient [3].…”

“…APAP is metabolically activated in the liver by cytochrome P450 enzymes, mostly Cyp2e1, which forms protein adducts leading to oxidative stress, activates c-jun N-terminal kinase (JNK) in the cytoplasm, induces its translocation to mitochondria and further enhances oxidative stress that finally causes cell death [2]. Despite extensive research on the mechanisms of APAP-induced hepatotoxicity, only one antidote, N-acetylcysteine (NAC), is approved for clinical application [3]. NAC helps to restore glutathione (GSH) in hepatocytes, and is maximally effective only when given within 8 hours after APAP ingestion [4].…”

Novel Therapies for the Treatment of Drug-Induced Liver Injury: A Systematic Review

“…Fomepizole is not only effective in preclinical animal experiments but also in human hepatocytes, in human volunteers, and patients with paracetamol-induced liver injury (Akakpo et al, 2020 fomepizole inhibited CYP2E1, blocked paracetamol activation, and N-acetyl-p-benzoquinone imine (NAPQI) formation, and downstream pathways that lead to necrosis of hepatocytes (Akakpo et al, 2018). Based on these results, a clinical crossover study with healthy volunteers given 80 mg/kg paracetamol with or without fomepizole (15 mg/kg intravenously) was performed (Kang et al, 2020).…”

“…The limitation of the further therapeutic use of fomepizole is that the drug has to be administered as early as possible as the therapeutic window is limited to the drug metabolism phase (Akakpo et al, 2020).…”

Kahweol Protects against Acetaminophen-Induced Hepatotoxicity in Mice through Inhibiting Oxidative Stress, Hepatocyte Death, and Inflammation

“…Because APAP-induced hepatotoxicity is associated with high mortality [2], much effort has been put into developing therapeutic approaches for this disease. However, to date, Nacetylcysteine (NAC) is the only treatment for APAP toxicity [4]. Administration of this drug at an early stage ameliorates APAP-induced hepatotoxicity by replenishing depleted GSH levels and preventing the accumulation of NAPQI.…”