Department of Cardiovascular Pharmacotherapy and Toxicology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan.
Yao Tokusyukai General Hospital, 1-17 wakakusacho, Yao, Osaka, 581-0011, Japan.
Biopharm Drug Dispos. 2022 Jun;43(3):108-116. doi: 10.1002/bdd.2316. Epub 2022 May 17.
Acetaminophen (APAP)-induced liver injury (AILI) is the most common cause of acute liver failure. Although the mechanisms that trigger AILI are well known, it is less understood how to halt AILI progression and facilitate liver recovery. Therefore, it is necessary to understand the pathophysiology of APAP hepatotoxicity in patients and to examine predictive/preventive markers. In a clinical study, we had a case in which aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels increased in a patient with a low ratio of APAP glucuronide concentration (AP-G)/APAP plasma concentration. Then a reverse translational study was conducted for clarifying this clinical question. The relationship between plasma AP-G/APAP concentration ratio and the levels of AST and ALT was examined by in vivo and in vitro experiments. In in vivo experiments, 10-week-old rats showed lower UGT activity, lower AP-G/APAP concentration ratios, and higher AST and ALT levels than 5-week-old rats. This suggests an inverse correlation between the AP-G/APAP concentration ratio and the AST, ALT levels in APAP-treated rats. Furthermore, as a result of the in vitro experiment, it was confirmed that the cell viability decreased when the AP-G/APAP concentration ratio in the culture medium decreased. Since the decrease in the plasma AP-G/APAP concentration ratio appears earlier than the increase of AST and ALT levels, the ratio might be a presymptomatic marker of AILI. When APAP is used for a long time, it is recommended to perform therapeutic drug monitoring of the AP-G/APAP concentration ratio, which is a predictive/preventive marker of AILI.
对乙酰氨基酚（APAP）诱导的肝损伤（AILI）是急性肝衰竭最常见的原因。虽然触发 AILI 的机制众所周知，但如何阻止 AILI 进展并促进肝脏恢复的机制尚不清楚。因此，有必要了解患者中 APAP 肝毒性的病理生理学，并检查预测/预防标志物。在一项临床研究中，我们遇到了这样一个病例，即一名患者的天门冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）水平升高，而其对乙酰氨基酚葡萄糖醛酸结合物浓度（AP-G）/对乙酰氨基酚血浆浓度的比值较低。然后进行了一项反向转化研究来阐明这个临床问题。通过体内和体外实验研究了血浆 AP-G/APAP 浓度比与 AST 和 ALT 水平之间的关系。在体内实验中，10 周龄大鼠的 UGT 活性、AP-G/APAP 浓度比以及 AST 和 ALT 水平均低于 5 周龄大鼠。这表明 APAP 处理大鼠的 AP-G/APAP 浓度比与 AST、ALT 水平呈负相关。此外，由于体外实验证实当培养基中的 AP-G/APAP 浓度比降低时，细胞活力降低。由于血浆 AP-G/APAP 浓度比的降低早于 AST 和 ALT 水平的升高，因此该比值可能是 AILI 的早期症状标志物。当长时间使用 APAP 时，建议进行 AP-G/APAP 浓度比的治疗药物监测，这是 AILI 的预测/预防标志物。
