Metabolism and pharmacokinetic studies of JPH203, an L-amino acid transporter 1 (LAT1) selective compound

Drug Metab Pharmacokinet. 2012;27(1):155-61. doi: 10.2133/dmpk.dmpk-11-rg-091. Epub 2011 Sep 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Antineoplastic Agents / analysis
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / pharmacokinetics*
  • Benzoxazoles / analysis
  • Benzoxazoles / blood
  • Benzoxazoles / metabolism
  • Benzoxazoles / pharmacokinetics*
  • Biotransformation
  • Dogs
  • Humans
  • Intestine, Small / metabolism
  • Kidney / chemistry
  • Kidney / metabolism
  • Large Neutral Amino Acid-Transporter 1 / chemistry*
  • Liver / chemistry
  • Liver / metabolism
  • Macaca fascicularis
  • Male
  • Membrane Transport Modulators / analysis
  • Membrane Transport Modulators / blood
  • Membrane Transport Modulators / metabolism*
  • Membrane Transport Modulators / pharmacokinetics*
  • Mice
  • Microsomes / metabolism*
  • Microsomes, Liver / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution
  • Tyrosine / analogs & derivatives*
  • Tyrosine / analysis
  • Tyrosine / blood
  • Tyrosine / metabolism
  • Tyrosine / pharmacokinetics

Substances

  • 2-amino-3-(4-((5-amino-2-phenylbenzo(d)oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic acid
  • Antineoplastic Agents
  • Benzoxazoles
  • Large Neutral Amino Acid-Transporter 1
  • Membrane Transport Modulators
  • Tyrosine