IDENTIFICATION OF THE SOLUBLE IN-VIVO METABOLITES OF INDIUM-111-DIETHYLENETRIAMINEPENTAACETIC ACID-D-PHE-OCTREOTIDE

Indium-111-diethylenetriaminepentaacetic Acid-D-phenylalanine(1)-octre otide (In-111-DTPA-octreotide) is a cyclic eight amino acid somatostat in analogue which is approved for gamma scintigraphy of neuroendocrine tumors. To address the factors that contribute to liver and kidney re tention of this radiopharmaceutical, its metabolism was evaluated in n ormal and tumor-bearing rats. The soluble fractions from nontarget Giv er and kidney) and target (tumor, pancreas, adrenals) organ homogenate s were analyzed out to 21 h postinjection, and urine was analyzed out to 12 h postinjection. The blood was analyzed at shorter time interval s due to the rapid clearance of In-111-DTPA-octreotide. Radio-TLC and HPLC were used to analyze organ homogenates, blood, and urine. By TLC, intact In-111-DTPA-octreotide was resolved from the soluble metabolit es, and a similar apparent rate of metabolism was observed in the live r, kidney, tumor, and pancreas with similar to 30% intact In-111-DTPA- octreotide at 4 h postinjection. In the adrenals, metabolism occurred more slowly with similar to 60% intact In-111-DTPA-octreotide at 4 h p ostinjection. At 4 h postinjection, the activity excreted in the urine consisted of 85% intact In-111-DTPA-octreotide. HPLC provided resolut ion of the individual extractable metabolites. In an attempt to identi fy these metabolites, two DTPA-amino acid sequences were synthesized: DTPA-D-Phe-Cys and DTPA-D-Phe. Under the conditions used for metabolit e analysis, In-111-DTPA-D-Phe-Cys-OH eluted at 14.6 min and In-111-DTP A-D-Phe-OH eluted at 7.0 min. Each of these standard sequences was com bined with the soluble portion of the organ homogenate and was shown b y HPLC to coelute with the metabolites. These data suggest that In-111 -DTPA-octreotide was initially degraded to In-111-DTPA-D-Phe-Cys-OH an d In-111-DTPA-D-Phe-OH. The In-111-DTPA-D-Phe-Cys-OH was further degra ded to In-111-DTPA-D-Phe-OH, which appeared to be the final metabolite that was extracted from the organs. From these results, it can be con cluded that at longer time points (>2 h postinjection) a significant a mount of In-111 was retained in nontarget organs as In-111-DTPA-D-Phe- OH and In-111-DTPA-Phe-Cys-OH and not as intact In-111-DTPA-octreotide .