论文部分内容阅读
Paracetamol(acetominophen,APAP) was administered orally in a rising dose protocol to 2 male and 2 female Cynomolgus monkeys to determine the Maximum Tolerated dose(MTD) for subsequent toxicology investigations.In the subsequent repeat dose study involving 6 monkeys,no dose-limiting toxicity was seen at up to 900 mg·kg-1.d-1 APAP for 14 d.Toxicokinetic analysis showed that plasma exposure rose,albeit less than proportionally,with increasing dose.There were some fluctuations in clinical chemistry and haematology parameters,but these were not dose-related,and there were no compound-related findings observed microscopically.Both monkeys at 900 mg·kg-1.d-1 had a 5 cm,gas filled segment in their large intestine that was considered compound-related.Metabolite profiling of the urine showed parent and glucuronidated APAP,but the cysteinyl conjugate which would be anticipated if the monkey has similar metabolism to rats and man was notably absent.This opens the possibility that metabolism in the cynomolgus monkey differs from that in the other species,and shows that the cynomolgus monkey is a poor model for investigating paracetamol-mediated toxicity in humans.
Paracetamol (acetominophen, APAP) was administered orally in a rising dose protocol to 2 male and 2 female Cynomolgus monkeys to determine the Maximum Tolerated Dose (MTD) for subsequently toxicology investigations. In the subsequent repeat dose study involving 6 monkeys, no dose-limiting toxicity was seen at up to 900 mg · kg-1.d-1 APAP for 14 d. Toxicokinetic analysis showed that plasma exposure rose, albeit less than proportionally, with increasing dose. There were some fluctuations in clinical chemistry and haematology parameters, but These were not dose-related, and there were no compound-related findings microscopically.Both monkeys at 900 mg · kg-1.d-1 had a 5 cm, gas filled segment in their large intestine that was considered compound-related. Metabolite profiling of the urine showed parent and glucuronidated APAP, but the cysteinyl conjugate which would be anticipated if the monkey has similar metabolism to rats and man was notably absent.This opens the possibility that metabolism in t he cynomolgus monkey differs from that in the other species, and shows that the cynomolgus monkey is a poor model for investigating paracetamol-mediated toxicity in humans.