Park Jeong M, Lin Yvonne S, Calamia Justina C, Thummel Kenneth E, Slattery John T, Kalhorn Thomas F, Carithers Robert L, Levy Adam E, Marsh Christopher L, Hebert Mary F
Department of Pharmacy, University of Washington, Seattle, WA, USA.
Clin Pharmacol Ther. 2003 Jun;73(6):545-53. doi: 10.1016/S0009-9236(03)00062-6.
Acetaminophen (INN, paracetamol) is metabolized to N-acetyl-p-benzoquinone imine (NAPQI), a hepatotoxic metabolite, predominantly by cytochrome P450 (CYP) 2E1. Alterations in drug metabolism occur after organ transplantation. This study was designed to characterize acetaminophen disposition during the first 6 months after liver transplantation.
Thirteen liver transplant patients received an oral dose of acetaminophen (500 mg) on days 2, 10, 90, and 180 after transplantation. Serial blood samples were collected for 8 hours, and urine was collected for 24 hours. Liver biopsy specimens were obtained from the donor liver during transplantation (day 0) and on days 10, 90, and 180 after transplantation.
There were significant time-dependent changes in acetaminophen metabolism after liver transplantation. When day 2 and day 10 were compared with day 180, the respective mean urinary recovery was 137% and 81% higher for thioether conjugates derived from NAPQI (P =.0002 and P =.01, respectively); 31% and 22% lower for acetaminophen sulfate (P =.0006 and P =.008, respectively); and 22% and 27% lower for acetaminophen glucuronide (P =.05 and P =.004, respectively). Metabolite formation clearances changed in concordance with the fractional urinary recovery. It was surprising that hepatic CYP2E1 content on day 10 after transplantation was only 20% higher, on average, than that found on day 180 (not significant). In contrast, hepatic CYP3A4 content was 984% higher, on average, when tissue from days 10 and 180 was compared after transplantation (P =.007).
Increased recovery of acetaminophen thioether conjugates during the first 10 days after liver transplantation was a result of impaired glucuronidation and sulfation and enhanced NAPQI formation.
对乙酰氨基酚（国际非专利药品名称，扑热息痛）主要通过细胞色素P450（CYP）2E1代谢为具有肝毒性的代谢产物N - 乙酰 - 对 - 苯醌亚胺（NAPQI）。器官移植后药物代谢会发生改变。本研究旨在描述肝移植后前6个月内对乙酰氨基酚的处置情况。
13例肝移植患者在移植后第2天、第10天、第90天和第180天口服一剂对乙酰氨基酚（500毫克）。连续采集8小时的血样，并采集24小时的尿液。在移植时（第0天）以及移植后第10天、第90天和第180天从供体肝脏获取肝活检标本。
肝移植后对乙酰氨基酚的代谢存在显著的时间依赖性变化。将第2天和第10天与第180天进行比较时，源自NAPQI的硫醚共轭物的平均尿回收率分别高出137%和81%（P分别为0.0002和0.01）；硫酸对乙酰氨基酚分别低31%和22%（P分别为0.0006和0.008）；对乙酰氨基酚葡萄糖醛酸分别低22%和27%（P分别为0.05和0.004）。代谢产物生成清除率的变化与尿回收率分数一致。令人惊讶的是，移植后第10天肝脏CYP2E1含量平均仅比第180天高20%（无显著性差异）。相比之下，将移植后第10天和第180天的组织进行比较时，肝脏CYP3A4含量平均高出984%（P = 0.007）。
肝移植后前10天内对乙酰氨基酚硫醚共轭物回收率增加是葡萄糖醛酸化和硫酸化受损以及NAPQI生成增强的结果。
