title: Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey.
abstract: 1. Paracetamol overdose remains the leading cause of acute liver failure in humans. This study was undertaken in cynomolgus monkeys to study the pharmacokinetics, metabolism and the potential for hepatotoxic insult from paracetamol administration as a possible model for human toxicity. 2. No adverse effects were observed for doses of up to 900 mg/kg/d for 14 d. Only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase in a number of animals were observed, with no clear dose response. 3. Toxicokinetic analysis showed good plasma exposure, albeit with less than proportional rises in Cmax and AUC, with increasing dose. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31-44% of human subjects. 4. Metabolite profiling of urine by (1)H NMR spectroscopy revealed paracetamol and its glucuronide and sulphate metabolites. Glutathione-derived metabolites, e.g. the cysteinyl conjugate, were only present in very low concentrations whilst the mercapturate was not detected. 5. These in vivo observations demonstrated that the cynomolgus monkey is remarkably resistant to paracetamol-induced toxicity and a poor model for investigating paracetamol-related hepatotoxicity in humans.
authors.affiliation: Centre for Drug Safety and Research (CDSER), Shanghai Institute of Materia Medica (SIMM) , Pudong, Shanghai , PR China .
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Nigel
authors.initials: N
authors.lastname: Barrass
authors.forename: Sonya
authors.initials: S
authors.lastname: Gales
authors.forename: Eva
authors.initials: E
authors.lastname: Lenz
authors.forename: Tony
authors.initials: T
authors.lastname: Parry
authors.forename: Helen
authors.initials: H
authors.lastname: Powell
authors.forename: Dale
authors.initials: D
authors.lastname: Thurman
authors.forename: Michael
authors.initials: M
authors.lastname: Hutchison
authors.forename: Ian D
authors.initials: ID
authors.lastname: Wilson
authors.forename: Luke
authors.initials: L
authors.lastname: Bi
authors.forename: Junwen
authors.initials: J
authors.lastname: Qiao
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Qin
authors.forename: Jin
authors.initials: J
authors.lastname: Ren
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: D000082:Acetaminophen
keywords: Cynomolgus monkeys; detoxification by glucuronidation; paracetamol toxicity