An artificial amino acid, 4-iodo-L-meta-tyrosine: biodistribution and excretion via kidney.
We evaluated the use of radiolabeled 4-iodo-L-meta-tyrosine as an amino acid transport marker. The pharmacologic features of this compound, particularly the biodistribution and excretion, were examined by conducting in vivo and in vitro studies using 4-(125)I-iodo-L-meta-tyrosine (4-(125)I-mTyr). Results obtained for L-(14)C-Tyr and 3-(125)I-iodo-alpha-methyl-L-tyrosine ((125)I-IMT) were used for comparison.


METHODS
In vivo biodistribution studies of 4-(125)I-mTyr were performed in male ddY mice. Urinary excretion of 4-(125)I-mTyr and (125)I-IMT with administration of probenecid was studied. Local distribution of 4-(125)I-mTyr and (125)I-IMT in kidney was visualized by autoradiography. We performed metabolite analysis of 4-(125)I-mTyr in mice. For in vitro studies, reabsorption mechanisms of 4-(125)I-mTyr were compared with those of (125)I-IMT and the parent L-(14)C-Tyr using superconfluent monolayers of the porcine kidney epithelial cell line LLC-PK(1) in medium containing inhibitor (L-Tyr, D-Tyr, and 2,4-dinitrophenol), in Na(+)-free medium, and at 4 degrees C.


RESULTS
4-(125)I-mTyr demonstrated high accumulation in the pancreas and kidney and comparable brain uptake to that of (125)I-IMT. Blood clearance of 4-(125)I-mTyr was faster than that of (125)I-IMT. Three hours after administration, >70% of 4-(125)I-mTyr was excreted via the urine, whereas <5% was found in the feces. Renal autoradiography revealed moderate accumulation of 4-(125)I-mTyr and high accumulation of (125)I-IMT in the renal cortex. Probenecid further reduced accumulation of 4-(125)I-mTyr and (125)I-IMT in the kidney as well as urinary excretion. At 30 min after tracer injection, intact free 4-(125)I-mTyr accounted for >98.1% of the total present in kidney and >96.3% in urine. Protein incorporation was not observed. Uptake of 4-(125)I-mTyr into LLC-PK(1) cell monolayers was remarkably reduced by 5 mmol/L L-Tyr (4.6%) and incubation at 4 degrees C (15.6%) but was reduced by 5 mmol/L D-Tyr (50.0%). L-(14)C-Tyr and (125)I-IMT showed similar results; however, uptake of (125)I-IMT was enhanced by 0.1 mmol/L 2,4-dinitrophenol (165.1%), an inhibitor of generation of energy-rich phosphates.


CONCLUSIONS
The artificial amino acid 4-(125)I-mTyr demonstrated high metabolic stability, rapid blood clearance, rapid urinary excretion, and similar biodistribution to other radiolabeled L-Tyr analogs. 4-(125)I-mTyr can be a competitive substrate of L-Tyr reabsorption. However, 4-(125)I-mTyr demonstrates different pharmacologic features than those of (125)I-IMT, particularly in renal handling. 4-(125)I-mTyr may potentially be applied as a new amino acid transport marker.
Shikano
Naoto
N
Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan. sikano@ipu.ac.jp
Kawai
Keiichi
K
Flores
Leo Garcia
LG
Nishii
Ryuichi
R
Kubota
Nobuo
N
Ishikawa
Nobuyoshi
N
Kubodera
Akiko
A
D000596:Amino Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D001345:Autoradiography; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005240:Feasibility Studies; D005260:Female; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000652:urine; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008781:Methyltyrosines / Q000493:pharmacokinetics / Q000652:urine; D051379:Mice; D008815:Mice, Inbred Strains; D009928:Organ Specificity; D011339:Probenecid / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013552:Swine; D014018:Tissue Distribution; D014443:Tyrosine / Q000493:pharmacokinetics / Q000652:urine
D000596:Amino Acids; D002250:Carbon Radioisotopes; D007457:Iodine Radioisotopes; D008781:Methyltyrosines; D014443:Tyrosine; C030855:3-iodo-alpha-methyltyrosine; D011339:Probenecid