Title
Metabolism and Pharmacokinetic Studies of JPH203, an L-Amino Acid Transporter 1 (LAT1) Selective Compound
Document Type
Article
Publication Date
1-1-2012
Description
Summary: 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.
Citation Information
Wempe, Michael F.; Rice, Peter J.; Lightner, Janet W.; Jutabha, Promsuk; Hayashi, Michinari; Anzai, Naohiko; Wakui, Shin; Kusuhara, Hiroyuki; Sugiyama, Yuichi; and Endou, Hitoshi. 2012. Metabolism and Pharmacokinetic Studies of JPH203, an L-Amino Acid Transporter 1 (LAT1) Selective Compound. Drug Metabolism and Pharmacokinetics. Vol.27(1). 155-161. https://doi.org/10.2133/dmpk.DMPK-11-RG-091 ISSN: 1347-4367