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Disposition of Acetaminophen at 4, 6, and 8 g/day for 3 Days in Healthy Young Adults
Author(s) -
Gelotte C K,
Auiler J F,
Lynch J M,
Temple A R,
Slattery J T
Publication year - 2007
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100121
Subject(s) - glucuronidation , acetaminophen , tolerability , placebo , metabolite , clinical pharmacology , pharmacology , pharmacokinetics , adverse effect , glucuronide , chemistry , glucuronosyltransferase , medicine , microsome , biochemistry , enzyme , alternative medicine , pathology
The objective of this study was to determine the disposition and tolerability of 1, 1.5, and 2 g acetaminophen every 6 h for 3 days. Group I healthy adults received acetaminophen (4 then 6 g/day) or placebo; Group II received acetaminophen (4 then 8 g/day) or placebo. Acetaminophen and metabolites were measured in plasma and urine. Hepatic aminotransferases were measured daily. At steady state, acetaminophen concentrations were surprisingly lower than predicted from single‐dose data, although sulfate formation clearance (fCL) was lower as expected, indicating cofactor depletion with possible sulfotransferase saturation. In contrast, glucuronide fCL was unexpectedly higher , strongly suggesting glucuronosyltransferase induction. This is the first evidence that acetaminophen induces its own glucuronidation. No dose‐dependent differences were detected in fCL of thiol metabolites formed via cytochrome P 4502E1. Hepatic aminotransferases stayed within reference ranges, and the incidence and frequency of adverse events were similar for acetaminophen and placebo. Although dose‐dependence of acetaminophen disposition was reported previously, this study shows a novel finding of time‐dependent disposition during repeated dosing. Unexpected increases in glucuronide fCL more than offset decreases in sulfate fCL, thus increasing acetaminophen clearance overall. Thiol metabolite fCL remained constant up to 8 g/day. These findings have important implications in short‐term (3 day) tolerability of supratherapeutic acetaminophen doses in healthy adults. Clinical Pharmacology & Therapeutics (2007) 81 , 840–848. doi: 10.1038/sj.clpt.6100121 ; published online 21 March 2007