Gastrointestinal, liver, and lung extraction ratio of acetaminophen in the rat after high dose administration

The pharmacokinetics of acetaminophen was examined in rats after administration of a single dose of 200 mg kg-1 by the intra-arterial, intravenous, portal vein, and oral routes. Levels of acetaminophen and its two major metabolites, acetaminophen-glucuronide and acetaminophen-sulfate, were quantitated in plasma at various time points for about 5 h after drug administration. The relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction ratio (first-pass effect after oral absorption) was determined. A mean oral extraction ratio of 0.49 was obtained. The mean relative extraction ratio of the gastrointestinal tract, liver, and lung were 0.52, 0.07, and 0, respectively, indicating a major contribution due to the gastrointestinal tract. This is in contrast to earlier studies which have indicated negligible contribution by the gastrointestinal tract to the oral first-pass effect when lower doses were utilized. These results suggest that the relative contribution of the gastrointestinal tract and liver to the oral first-pass effect of acetaminophen may be dose-dependent.