In adults, the primary metabolic pathway for paracetamol is glucuronidation. This yields a relatively non-toxic metabolite, which is excreted into bile and passed out of the body. A small amount of the drug is metabolized via the cytochrome P-450 pathway (to be specific, CYP3A4 and CYP2E1) into NAPQI, which is extremely toxic to liver tissue, as well as being a strong biochemical oxidizer. In an average adult, only a small amount (approximately 10% of a therapeutic paracetamol dose) of NAPQI is produced, which is inactivated by conjugation with glutathione (GSH). The amount of NAPQI produced differs in certain populations.
The minimum dosage at which paracetamol causes toxicity usually is 7.5 to 10g in the average person. The lethal dose is usually between 10 g and 15 g. Concurrent alcohol intake lowers these thresholds significantly. Chronic alcoholics may be more susceptible to adverse effects due to reduced glutathione levels. Other populations may experience effects at lower or higher dosages depending on differences in P-450 enzyme activity and other factors which affect the amount of NAPQI produced. In general, however, the primary concern is accidental or intentional paracetamol overdose.
When a toxic dose of paracetamol is ingested, the normal glucuronide pathway is saturated and large amounts of NAPQI are produced. Liver reserves of glutathione are depleted by conjugation with this excess NAPQI. The mechanism by which toxicity results is complex, but is believed to involve reaction between unconjugated NAPQI and critical proteins as well as increased susceptibility to oxidative stress caused by the depletion of glutathione.