Dose-dependent pharmacokinetics and first-pass metabolism of acetaminophen in rats.

In order to investigate the in vivo first-pass metabolism of acetaminophen (AAP) following the oral and intraduodenal administration in rats, a pharmacokinetic compartment model including absorption process was developed. Using the parameters for the disposition kinetics of AAP and its metabolites, sulfate and glucuronide, which were determined in the separate study, the extent of the first-pass metabolism and the contribution of sulfation and glucuronidation to the total first-pass metabolism in vivo were quantitatively estimated. As for the results, the first-pass metabolism of AAP following the oral and intraduodenal administration was mainly attributable to the sulfo-conjugation pathway in rats. The sulfation of AAP in the intestine and/or in the liver during the first-pass was proved to be a saturable process. Then, the sulfation in the first-pass metabolism showed the dose- and absorption rate-dependent kinetics. Thus, the pharmacokinetic model including the absorption process proposed in the present study was proved to be valid and useful for the estimation of in vivo first-pass metabolism of AAP in rats.