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 ab...

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Bibliographic Details
Published in:Biological & pharmaceutical bulletin 1996/01/15, Vol.19(1), pp.77-82
Main Authors: SAWAMOTO, Taiji, KUROSAKI, Yuji, KIMURA, Toshikiro, NAKAYAMA, Taiji
Format: Article
Language:English
Subjects:
acetaminophen
Acetaminophen - administration & dosage
Acetaminophen - blood
Acetaminophen - pharmacokinetics
acetaminophen sulfate
Administration, Oral
Analgesics
Analgesics, Non-Narcotic - administration & dosage
Analgesics, Non-Narcotic - blood
Analgesics, Non-Narcotic - pharmacokinetics
Animals
Biological and medical sciences
Chromatography, High Pressure Liquid
Colon - metabolism
Injections, Intravenous
Intestinal Absorption
Male
Medical sciences
microflora
Neuropharmacology
pharmacokinetics
Pharmacology. Drug treatments
rat
Rats
Rats, Wistar
Sulfates - pharmacokinetics
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Summary: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.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.19.77