Showa Pharmaceutical University.
J Toxicol Sci. 2020;45(11):695-700. doi: 10.2131/jts.45.695.
Coumarin is a dietary-derived substance that is extensively metabolized by human liver to excretable 7-hydroxycoumarin. Although coumarin under daily dietary consumption is generally regarded as nontoxic, the substance is of toxicological and clinical interest because of its potential association with hepatotoxicity, which is especially evident in rats. In this study, the pharmacokinetics of coumarin were modeled after virtual oral administration in humans. The adjusted monitoring equivalents of coumarin, along with the biotransformation of coumarin to o-hydroxyphenylacetic acid (via 3,4-epoxidation) based on reported plasma concentrations from rat studies, were scaled to human coumarin equivalents using known species allometric scaling factors. Using rat and human liver preparations, data on the rapid in vitro metabolic clearance for humans (~50-fold faster than in rats) were obtained for in vitro-in vivo extrapolation. For human physiologically based pharmacokinetic (PBPK) modeling, the metabolic ratios to o-hydroxyphenylacetic acid and 7-hydroxycoumarin were set at minor (0.1) and major (0.9) levels for the total disappearance of coumarin. The resulting modeled plasma concentration curves in humans generated by simple PBPK models were consistent with reported simulated coumarin maximum concentrations. These results provide basic information to simulate plasma levels of coumarin and its primary metabolite 7-hydroxycoumarin or its secondary activated metabolite o-hydroxyphenylacetic acid (via 3,4-epoxidation) resulting from dietary foodstuff consumption. Under the current assumptions, little toxicological impact of coumarin was evident in humans, thereby indicating the usefulness of forward dosimetry using PBPK modeling for human risk assessment.
香豆素是一种来源于饮食的物质，在人体肝脏中被广泛代谢为可排泄的 7-羟基香豆素。虽然日常饮食中摄入的香豆素通常被认为是无毒的，但由于其与肝毒性的潜在关联，该物质具有毒理学和临床意义，尤其是在大鼠中。在这项研究中，模拟了人体虚拟口服香豆素后的药代动力学。根据大鼠研究中的报告血浆浓度，将香豆素的调整监测等效物以及香豆素向邻-羟基苯乙酸（通过 3,4-环氧化）的生物转化，与人类香豆素等效物进行了比例换算，使用已知的物种比例缩放因子。使用大鼠和人肝制剂，获得了用于体外-体内外推的人体快速体外代谢清除率的数据（比大鼠快约 50 倍）。对于人体基于生理学的药代动力学（PBPK）建模，设定代谢比值为邻-羟基苯乙酸和 7-羟基香豆素分别为 minor（0.1）和 major（0.9），用于香豆素的总消除。简单的 PBPK 模型生成的人体模拟血浆浓度曲线与报告的模拟香豆素最大浓度一致。这些结果为模拟香豆素及其主要代谢物 7-羟基香豆素或其次级激活代谢物邻-羟基苯乙酸（通过 3,4-环氧化）的血浆水平提供了基本信息，这些代谢物来自饮食食品的消费。根据当前的假设，香豆素在人体内没有明显的毒理学影响，从而表明使用 PBPK 建模进行人体风险评估的正向剂量测定是有用的。
