Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey

doi:10.3109/00498254.2014.973000

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	Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey
	Yu, Hong 1; Barrass, Nigel 2; Gales, Sonya 2; Lenz, Eva 2; Parry, Tony 2; Powell, Helen 2; Thurman, Dale 2; Hutchison, Michael 2; Wilson, Ian D.2; Bi, Luke 3
刊名	XENOBIOTICA
	2015-03
卷号	45 期号:3 页码:270-277
关键词	Cynomolgus monkeys detoxification by glucuronidation paracetamol toxicity
ISSN号	0049-8254
DOI	10.3109/00498254.2014.973000
文献子类	Article
英文摘要	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 C-max and AUC, with increasing dose. The C-max 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 H-1 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.
WOS关键词	ACUTE LIVER-FAILURE ; OXIDATIVE STRESS ; DRUG-METABOLISM ; RHESUS-MONKEY ; PHASE-I ; INJURY ; RATS ; DOG ; GLUCURONIDATION ; GLUTATHIONE
WOS研究方向	Pharmacology & Pharmacy ; Toxicology
语种	英语
出版者	INFORMA HEALTHCARE
WOS记录号	WOS:000350451700011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276625]
专题	药物安全性评价中心
通讯作者	Lenz, Eva
作者单位	1.SIMM, Ctr Drug Safety & Res CDSER, Shanghai, Peoples R China; 2.AstraZeneca UK Ltd, DSM Dept, Macclesfield SK10 4TG, Cheshire, England; 3.Covance Pharmaceut R&D Shanghai Co Ltd, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Yu, Hong,Barrass, Nigel,Gales, Sonya,et al. Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey[J]. XENOBIOTICA,2015,45(3):270-277.
APA	Yu, Hong.,Barrass, Nigel.,Gales, Sonya.,Lenz, Eva.,Parry, Tony.,...&Ren, Jin.(2015).Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey.XENOBIOTICA,45(3),270-277.
MLA	Yu, Hong,et al."Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey".XENOBIOTICA 45.3(2015):270-277.