Lack of effect of cimetidine on acetaminophen disposition in humans

Abstract

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.

Protective Effect of Chlormethiazole , a Sedative , against Acetaminophen - Induced Liver Injury in Mice

“…However, the dose given in that experiment was 120 mg/kg, 18 times higher than the usual therapeutic dose in humans 18 ) . Additionally, studies performed with human microsome suggested a need for 5–10 times higher cimetidine concentrations than putative therapeutic concentrations 24 ) . Subsequent clinical trials have failed to prove the efficacy of cimetidine against acetaminophen-induced hepatic injury in humans 20 , 25 ) .…”

Cimetidine as an alternative to N‐acetylcysteine in patients with paracetamol poisoning

“…From animal studies carried out in the early 1980s, cimetidine was reported to protect the liver against paracetamol toxicity 7,8,9 . Subsequent reports on human subjects were not as encouraging, perhaps owing to the low doses of cimetidine that were trialed 10,11,12 . However, if the doses used on animals are extrapolated, a minimum infusion of 40mg/kg is needed.…”

Disposition of acetaminophen and indocyanine green in cystic fibrosis-knockout mice

“…Because the glucuronidation of APAP at the dose used in the study is unlikely to be rate-limited by the availability of the cofactor UDP glucuronic acid (23,24), increased glucuronidation of APAP in the CF-knockout mice may be attributable to an induction or activation of UGT. Preliminary in vitro studies of APAP glucuronidation using mouse liver microsomes suggest no apparent difference in either Vm or Km for metabolism of APAP by UGT.…”