Pharmacokinetics of 3-[125I]iodo-alpha-methyl-L-tyrosine, a tumor imaging agent, after probenecid loading in mice implanted with colon cancer DLD-1 cells.
BACKGROUND
In order to improve tumor imaging, changes in the pharmacokinetics of 3-[123I]iodo-alpha-methyl-l-tyrosine ([123I]IMT), an artificial amino acid that exhibits high tumor accumulation, after probenecid (PBC) loading was studied in mice implanted with colon cancer DLD-1 cells using 125I-labeled IMT ([125I]IMT).


METHODS
DLD-1-implanted KSN-slc nude male mice received 740 kBq of [125I]IMT via the tail vein at 5 min after 50 mg/kg body weight PBC loading, and autoradiography was performed at 5, 15 and 30 min after injection. Male ddY mice then received 670 kBq of [125I]IMT and 50 mg/kg 2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid (BCH) or p-aminohippurate (PAH) via the tail vein, and kidney autoradiography was performed at 5 min after injection. In vitro inhibition study was then performed based on the accumulation mechanisms of [125I]IMT in DLD-1, using 1 mM l-tyrosine, BCH, alpha-(methylamino)-isobutyric acid, N-benzoyl-beta-alanine, PBC, PAH, 2,4-dinitrophenol and sodium azide. Both Na+-dependent and Na+-independent uptake were investigated.


RESULTS
Higher tumor accumulation in PBC-loaded DLD-1-implanted mice was seen when compared to control mice. PAH and BCH, respectively, reduced renal accumulation in the tubule segment-2 (S2)-like and S1-like regions. We confirmed that [125I]IMT transport is predominantly mediated by l-type amino acid transporter-1 in DLD-1 cells.


CONCLUSIONS
[125I]IMT uptake is mediated by organic anion and amino acid transporters in the kidney. Organic anion transporter inhibitors may yield better tumor images with good tumor/normal tissue radioactivity ratios if adequate administration plans are developed.
Nakajima
Syuichi
S
Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan.
Shikano
Naoto
N
Kotani
Takashi
T
Ogura
Masato
M
Nishii
Ryuichi
R
Yoshimoto
Mitsuyoshi
M
Yamaguchi
Naoto
N
Iwamura
Yukio
Y
Kubota
Nobuo
N
Ishikawa
Nobuyoshi
N
Kawai
Keiichi
K
D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D007668:Kidney / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008781:Methyltyrosines / Q000493:pharmacokinetics*; D051379:Mice; D009928:Organ Specificity / Q000187:drug effects; D011339:Probenecid / Q000008:administration & dosage*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution / Q000187:drug effects; D014528:Uricosuric Agents / Q000008:administration & dosage
D008781:Methyltyrosines; D019275:Radiopharmaceuticals; D014528:Uricosuric Agents; C030855:3-iodo-alpha-methyltyrosine; D011339:Probenecid