Age-dependent changes in first-pass metabolism of acetaminophen in rats

The contribution of gastrointestinal tract (GIT), liver, and lung towards the first-pass metabolism of acetaminophen was examined using 3-week-old, 10-week-old and 1-year-old rats after administration of 30 mg kg-1 doses by intra-arterial, intravenous, intraperitoneal, and oral routes. Plasma concentrations of acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5h after drug administration. Total oral extraction of acetaminophen was extensive in 10-week-old and 1-year-old rats (Eo = 0.46) and the major contribution to the overall first-pass metabolism was due to the GIT (Eg = 0.50-0.53). Oral extraction in 3-week-old rats was minimal (Eo = 0.10) and there did not appear to be an extraction by the GIT (Eg = 0.00). These results suggest that the ability of GIT to metabolize acetaminophen to glucuronide and sulfate is undeveloped in the infant rats. No changes in the contribution of different organs to the first-pass metabolism of acetaminophen was observed 10 weeks after birth. Pharmacokinetic parameters for acetaminophen in infant rats (3-week-old) and 10-week-old rats were similar after drug administration by the intra-arterial and intravenous routes.