School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
Drug Metab Pharmacokinet. 2012;27(1):155-61. doi: 10.2133/dmpk.dmpk-11-rg-091. Epub 2011 Sep 13.
Many primary human tumors and tumor cell lines highly express human L-type amino acid transporter 1 (hLAT1); cancerous cells in vivo are strongly linked to LAT1 expression. Synthetic chemistry and in vitro screening efforts have afforded a variety of novel and highly hLAT1 selective compounds, such as JPH203 1. In a recent report, we demonstrated that 1 has potent in vitro and in vivo activity. JPH203 was intravenously administered to produce significant growth inhibition against HT-29 tumors transplanted in nude mice. The current work develops a robust LC/MS-MS method to monitor 1 and its major Phase II metabolite N-acetyl-JPH203 2 from biological samples. We have conducted in vitro and in vivo experiments and the major scientific findings are: i) the major route of biotransformation of 1 is Phase II metabolism to produce 2; ii) metabolite 2 is formed in various organs/tissues (i.e. blood, liver, kidney); and iii) as dogs, which are deficient in NAT genes, do not produce 2, the dog will not be an appropriate toxicological model to evaluate 1.
许多原发性人类肿瘤和肿瘤细胞系高度表达人 L 型氨基酸转运蛋白 1（hLAT1）；体内的癌细胞与 LAT1 的表达密切相关。合成化学和体外筛选工作提供了多种新型的、高度 hLAT1 选择性化合物，如 JPH2031。在最近的一份报告中，我们证明了 1 具有很强的体外和体内活性。JPH203 通过静脉注射给药，对裸鼠移植的 HT-29 肿瘤产生了显著的生长抑制作用。本工作开发了一种强大的 LC/MS-MS 方法来监测生物样本中的 1 和其主要的 II 期代谢物 N-乙酰-JPH2032。我们进行了体外和体内实验，主要的科学发现是：i）1 的主要生物转化途径是产生 2 的 II 期代谢；ii）代谢物 2 形成于各种器官/组织（即血液、肝脏、肾脏）；iii）由于狗缺乏 NAT 基因，不会产生 2，因此狗不会成为评估 1 的合适的毒理学模型。
