First-pass metabolism of acetaminophen in rats after low and high doses

The first-pass metabolism of acetaminophen was examined in rats after the administration of 15, 30, 150, and 300 mg kg-1 doses by intra-arterial, intravenous, portal vein, and oral routes. Plasma concentrations of acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5 h after drug administration. The first-pass effect after oral administration (oral extraction) was extensive (Eo = 0.34-0.50) at all doses administered. Calculation of the relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction of acetaminophen indicated that the major contribution was due to the gastrointestinal tract at all doses studied (Eg = 0.33-0.50). At higher doses (150 and 300 mg kg-1) clearance was lower possibly due to the saturation of acetaminophen sulfate formation. However, even at these high doses, the contribution of the gastrointestinal mucosa to the oral extraction remained unchanged. Therefore, it appears that the apparent dose-dependent characteristics of acetaminophen metabolism may be due to the saturation of acetaminophen sulfate formation in the liver.