Evaluation of the Efficacy of Fomepizole in the Treatment of Acetaminophen Overdose

Acetaminophen (N-acetyl-p-aminophenol, paracetamol, APAP) is a commonly used analgesic and antipyretic. The maximal recommended therapeutic dose of 4 g per day is safe and is well tolerated. Unintentional and intentional overdoses occur and can cause serious hepatotoxicity. Acetaminophen overdose is the most common cause of drug-induced acute liver failure (ALF) in the US, accounting for 46% of all cases, which results in about 300-500 deaths annually. This is a persistent health problem because acetaminophen is widely available in the US market. Acetaminophen overdose can induce acute liver failure by a process that involves two processes: oxidative metabolism and amplification of oxidant stress.

Oxidative metabolism: At therapeutic doses, 95% of APAP is metabolized via glucuronidation and sulfation in the liver and eliminated from the body without resulting toxicity. In addition to these pathways, approximately 5% of an acetaminophen dose is metabolized by cytochrome P450 enzymes (mainly CYP2E1), which results in the formation of a highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). During appropriate use of acetaminophen at therapeutic doses, the small amount of NAPQI produced is readily detoxified by intracellular glutathione. After an acetaminophen overdose, a much larger amount of acetaminophen is oxidized by CYP2E1 resulting in elevated amounts of NAPQI. When the amount of NAPQI generated exceeds hepatic glutathione stores, NAPQI binds to cellular and mitochondrial proteins causing dysfunction. This cascade can be amplified through other mediators leading to DNA damage and hepatocyte death.

Amplification of oxidant stress: After NAPQI formation, c-Jun N-terminal kinase (JNK) activation in the cytosol of the cell and its mitochondrial translocation results in the induction of the mitochondrial membrane transition pore. This ultimately triggers a molecular cascade causing amplification of mitochondrial oxidant stress, nuclear DNA fragmentation, and hepatic cell death.

Acetylcysteine is the only FDA approved drug indicated for clinical use in acetaminophen overdose. It is highly effective when patients seek medical attention within 8 hours of acute single ingestion. The incidence and severity of clinically important liver injury after acute ingestion of acetaminophen increases when acetylcysteine is started over 8 hours after ingestion. Many patients, however, seek medical attention later, when acetylcysteine has reduced efficacy thus putting some patients at risk of developing hepatotoxicity, fulminant hepatic failure and death despite acetylcysteine therapy. While not a frequent occurrence, the effects are devastating to the patient and their family. Acetylcysteine acts by replenishing reduced glutathione, but it only addresses the oxidative phase of acetaminophen toxicity. A novel therapeutic intervention strategy is needed for the treatment of acetaminophen-induced hepatotoxicity in these higher risk patients.