Acetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations
Acetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations
复制标题
DOI：
10.1007/s00228-012-1410-7
复制
发表时间：
2013-04-01
影响因子：
2.9
通讯作者：
Roberts, Dean
中科院分区：
文献类型：
--
作者：
James, Laura P.;Chiew, Angela;Roberts, Dean
对乙酰氨基酚（APAP）蛋白加合物是APAP代谢的生物标志物，反映了APAP的氧化和反应性代谢产物N-乙酰基-对苯醌亚胺的产生。高水平的加合物对应于APAP相关急性肝衰竭患者的肝毒性。低剂量暴露于APAP后的加合物形成尚未得到充分研究。APAP蛋白加合物是从参加APAP交叉研究的禁食个体采集的血液样本中测量的。使用经验证的高效液相色谱电化学检测（HPLC-EC）对所有给药后血样中的加合物进行定量。加合物的药代动力学参数的比较没有揭示ER和IR制剂之间的显著差异，有一个例外。IR的加合物形成速率分别比ER制剂快（0.420 +/- 0.157对0.203 +/- 0.080 1/h）。IR和ER加合物的最大血药浓度（Cmax）分别为0.108（+/- 0.020）和0.100（+/- 0.028）nmol/ml血清，并且比先前报道的继发于APAP的急性肝功能衰竭的成人中的加合物水平低两个数量级。与急性肝功能衰竭相关的疾病
Acetaminophen (APAP) protein adducts are a biomarker of APAP metabolism, reflecting oxidation of APAP and generation of the reactive metabolite N-acetyl-p-benzoquinone imine. High levels of adducts correspond to liver toxicity in patients with APAP-related acute liver failure. Adduct formation following low-dose exposure to APAP has not been well studied. APAP protein adducts were measured in blood samples collected from fasted individuals who participated in a crossover study of APAP (80 mg/kg) comparing extended release (ER) and immediate release (IR) formulations.Adducts were quantified in all postdose blood samples using a validated high-performance liquid chromatography electrochemical detection (HPLC-EC) assay.Comparison of pharmacokinetic parameters for adducts did not reveal significant differences between ER and IR formulations, with one exception. Formation rates for adducts were faster for IR than the ER formulation (0.420 +/- 0.157 vs. 0.203 +/- 0.080 1/h), respectively. Maximum plasma concentrations (C-max) of adducts for IR and ER were 0.108 (+/- 0.020) and 0.100 (+/- 0.028) nmol/ml serum, respectively, and were two orders of magnitude lower than adduct levels previously reported in adults with acute liver failure secondary to APAP.APAP protein adducts are rapidly formed following nontoxic ingestion of APAP at levels significantly lower than those associated with acute liver failure.