Biopharmaceutical Studies on Drug/Conjugated-Metabolite Interactions. III. Effect of Acetaminophen Sulfate and Its Positional Isomers on the Pharmacokinetics of Acetaminophen in Rats

The effect of three positional isomers, o-, m- and p-acetylaminophenyl sulfate (AOAPS, AMAPS and APAPS (acetaminophen sulfate), respectively), on the pharmacokinetics of acetaminophen (APAP) was investigated in rats. All of the intravenously administered positional isomers were rapidly eliminated fr...

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Bibliographic Details
Published in:Biological & pharmaceutical bulletin 1997/05/15, Vol.20(5), pp.522-529
Main Authors: NAKAYAMA, Taiji, SAWAMOTO, Taiji, KARINO, Tadaaki, MATSUMURA, Miki, SASAKI, Kenji, KUROSAKI, Yuji, KIMURA, Toshihiro
Format: Article
Language:English
Subjects:
acetaminophen
Acetaminophen - analogs & derivatives
Acetaminophen - blood
Acetaminophen - metabolism
Acetaminophen - pharmacokinetics
Acetaminophen - pharmacology
acetaminophen sulfate
Analgesics
Analgesics, Non-Narcotic - blood
Analgesics, Non-Narcotic - metabolism
Analgesics, Non-Narcotic - pharmacokinetics
Animals
Binding, Competitive
Biological and medical sciences
Blood Proteins - metabolism
Drug Interactions
drug/conjugated-metabolite interaction
Isomerism
Male
Medical sciences
Neuropharmacology
pharmacokinetics
Pharmacology. Drug treatments
positional isomer
rat
Rats
Rats, Wistar
Structure-Activity Relationship
Sulfuric Acid Esters - blood
Sulfuric Acid Esters - pharmacology
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Summary:The effect of three positional isomers, o-, m- and p-acetylaminophenyl sulfate (AOAPS, AMAPS and APAPS (acetaminophen sulfate), respectively), on the pharmacokinetics of acetaminophen (APAP) was investigated in rats. All of the intravenously administered positional isomers were rapidly eliminated from plasma, and approximately 80% of the dose was excreted in an unchanged form in the urine within 4 h, while biliary excretions represented a small percent of the doses. Following the intravenous bolus injection of APAP, plasma elimination of APAP was accelerated and the distribution volume of APAP was increased under a steady state concentration (about 10 μg APAP eq/ml) of AOAPS or APAPS, but not AMAPS, as compared with saline infusion. Total body clearances of APAP were increased from 18.3 ml/min/kg for the control to 23.9 and 26.9 ml/min/kg for AOAPS and APAPS coadministration, respectively. AOAPS and APAPS competitively displaced the serum protein binding of APAP, while AMAPS had little effect. The distribution volume of unbound APAP was anomalously increased by APAPS, while it was not affected by AOAPS or AMAPS. Tissue-to-plasma concentration ratios of APAP were significantly increased by APAPS in the liver, kidney and brain, while they were only slightly increased by AOAPS. It was suggested that APAPS has nt only the displacing activity of serum protein binding but also other specific effectiveness on the distribution of APAP.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.20.522