title: Metabolism and pharmacokinetic studies of JPH203, an L-amino acid transporter 1 (LAT1) selective compound.
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.
authors.affiliation: School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA. Michael.Wempe@UCDenver.edu
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rice
authors.forename: Janet W
authors.initials: JW
authors.lastname: Lightner
authors.forename: Promsuk
authors.initials: P
authors.lastname: Jutabha
authors.forename: Michinari
authors.initials: M
authors.lastname: Hayashi
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.forename: Shin
authors.initials: S
authors.lastname: Wakui
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D001583:Benzoxazoles / Q000032:analysis / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D004285:Dogs; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000737:chemistry*; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D049990:Membrane Transport Modulators / Q000032:analysis / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D051379:Mice; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: C548172:2-amino-3-(4-((5-amino-2-phenylbenzo(d)oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic acid; D000970:Antineoplastic Agents; D001583:Benzoxazoles; D027283:Large Neutral Amino Acid-Transporter 1; D049990:Membrane Transport Modulators; D014443:Tyrosine