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Lack of effect of cimetidine on acetaminophen disposition in humans
Author(s) -
Slattery John T,
McRorie Teresa I,
Reynolds Rozanne,
Kalhorn Thomas F,
Kharasch Evan D,
Eddy A Craig
Publication year - 1989
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/clpt.1989.190
Subject(s) - cimetidine , acetaminophen , glucuronidation , pharmacology , volunteer , chemistry , metabolite , urine , glucuronide , clinical pharmacology , pharmacokinetics , microsome , medicine , biochemistry , enzyme , biology , agronomy
The effect of cimetidine administration on the disposition of acetaminophen was evaluated in seven men and six women. One gram of acetaminophen was administered to each volunteer after an overnight fast on two occasions in a balanced crossover design with and without cimetidine, 300 mg every 6 hours beginning 50 hours before acetaminophen administration and continuing for 22 hours after. N ‐Acetylcysteine was administered on both occasions when acetaminophen was ingested to protect against glutathione depletion. Blood samples were collected serially for 12 hours after acetaminophen administration, and total urine volume was collected for 24 hours. Fractional clearances of acetaminophen through renal and metabolic routes (sulfation, glucuronidation, 3‐hydroxylation, and glutathione conjugate formation) were not altered by cimetidine administration. Studies in microsomes prepared from two human organ donors indicated that cimetidine inhibited acetaminophen reactive metabolite formation noncompetitively, with Ki values of 0.35 mmol/L and 0.32 mmol/L for the respective livers, which is 5 to 10 times the putative cimetidine concentration required for therapeutic effect. Clinical Pharmacology and Therapeutics (1989) 46, 591–597; doi: 10.1038/clpt.1989.190