In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver
In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver
复制标题
DOI：
10.1002/jps.20783
复制
发表时间：
2007-02-01
影响因子：
3.8
通讯作者：
Yokoi, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Katoh, Miki;Sawada, Toshiro;Yokoi, Tsuyoshi
我们先前阐明，主要的人类药物代谢酶在最近建立的嵌合尿激酶型纤溶酶原激活剂（uPA）（+/+）/严重联合免疫缺陷（SCID）小鼠系中表达，其中肝脏可被人肝细胞取代80%以上。在本研究中，我们研究了CYP 2D 6底物debrisoquin（DB）在高（高）或低（低）人白蛋白（hAlb）浓度嵌合小鼠和对照uPA（-/-）/SCID小鼠中的体内药物代谢。小鼠血液中的hAlb是人源化肝脏的指标之一，因为嵌合小鼠产生hAlb。经口给予2.0 mg/kg DB后，高剂量组中DB的主要CYP 2D 6代谢产物4 '-羟基异喹（4-OH DB）的AUC（0-8）值是低剂量组和uPA（-/-）/SCID小鼠的3.6倍。通过使用典型的CYP 2D 6抑制剂奎尼丁进行预处理，高剂量组中4-OH DB的AUC（0-8）值降低，但低剂量组和uPA-/-/SCID小鼠中的AUC（0-8）值没有变化。体外动力学分析和奎尼丁对肝微粒体中DB 4 '-羟化酶活性的Ki值也支持嵌合小鼠的人源化。总之，嵌合小鼠表现出药物代谢和P450抑制的人源化特征。(c)2006 Wiley-Liss，Inc.
We previously clarified that major human drug metabolizing enzymes were expressed in a chimeric urokinase-type plasminogen activator (uPA)(+/+)/severe combined immunodeficient (SCID) mouse line established recently, in which the liver could be replaced by more than 80% with human hepatocytes. In the present study, we investigated the in vivo drug metabolism of a CYP2D6 substrate, debrisoquin (DB), in chimeric mice with high (High) or low (Low) human albumin (hAlb) concentrations and in control uPA(-/-)/SCID mice. The hAlb in the mouse blood is one of the indices of humanized liver because the chimeric mice produce hAlb. After oral administration of DB at 2.0 mg/kg, the AUC(0-8) value of a major CYP2D6 metabolite of DB, 4'-hydroxydebrisoquin (4-OH DB), in High was 3.6-fold higher than those of Low and uPA(-/-)/SCID mice. By pre-treatment with a typical CYP2D6 inhibitor, quinidine, the AUC(0-8) value of 4-OH DB in High was decreased although such values in Low and uPA-/-/SCID mice did not change. The in vitro kinetic analyses and the K-i values of quinidine on the DB 4'-hydroxylase activity in liver microsomes also supported the humanization of the chimeric mice. In conclusion, the chimeric mice exhibited a humanized profile of drug metabolism and the inhibition of P450. (c) 2006 Wiley-Liss, Inc.