Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
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Metabolism and Pharmacokinetic Studies of JPH203, an L-Amino Acid Transporter 1 (LAT1) Selective Compound
Michael F. WEMPEPeter J. RICEJanet W. LIGHTNERPromsuk JUTABHAMichinari HAYASHINaohiko ANZAIShin WAKUIHiroyuki KUSUHARAYuichi SUGIYAMAHitoshi ENDOU
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2012 Volume 27 Issue 1 Pages 155-161

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Abstract

  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.

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© 2012 by The Japanese Society for the Study of Xenobiotics
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