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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Pharmacokinetics of acetaminophen sulfate after oral administration in rats: analysis of plasma profiles exhibiting a non-linear second peak.

The pharmacokinetics of the two-peak plasma profiles of orally administered acetaminophen sulfate (APAPS), a major conjugated metabolite of acetaminophen (APAP), in rats was examined by a two-compartment model having two delivery routes with individual time lags: a direct delivery route of APAPS absorbed in an unchanged form and an indirect one where APAPS was absorbed as APAP after deconjugation in the lower intestine. Pharmacokinetic parameters were estimated by a non-linear least squares program, MULTI(FILT), based on the fast inverse Laplace transform algorithm. Plasma APAPS concentration profiles after oral doses were simulated satisfactorily. In a dose escalation study, the peroral availability of APAPS derived from the direct route was not changed significantly with the doses. However, that from the indirect route was decreased with the dose escalation, suggesting the contribution of a capacity-limited deconjugation of APAPS to APAP by the intestinal microflora to the non-linear pharmacokinetics of orally administered APAPS. The absorption of peroral APAPS in rats at a dose range of 30 to 120 mg APAP eq/kg could be summarized as follows: (1) approximately 25% (22 to 32%) of orally administered APAPS are absorbed from the gastrointestinal tract in an unchanged form; (2) more than 50% (50 to 98%) are deconjugated to APAP in the lower intestinal tract; and (3) the latter plays a significant role as an indirect and non-linear APAPS delivery system because considerable amounts of APAP thus absorbed are rapidly reconjugated to APAPS in the systemic circulation, which gives the second plasma APAPS peak.[1]


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