Identification of the soluble in vivo metabolites of indium-111-diethylenetriaminepentaacetic acid-D-Phe-octreotide

Indium-111-diethylenetriaminepentaacetic Acid-D-phenylalanine(1)-octreotide (In-111-DTPA-octreotide) is a cyclic eight amino acid somatostatin analogue which is approved for gamma scintigraphy of neuroendocrine tumors. To address the factors that contribute to liver and kidney retention of this radiopharmaceutical, its metabolism was evaluated in normal and tumor-bearing rats. The soluble fractions from nontarget Giver and kidney) and target (tumor, pancreas, adrenals) organ homogenates were analyzed out to 21 h postinjection, and urine was analyzed out to 12 h postinjection. The blood was analyzed at shorter time intervals 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 metabolites, and a similar apparent rate of metabolism was observed in the liver, 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 postinjection. At 4 h postinjection, the activity excreted in the urine consisted of 85% intact In-111-DTPA-octreotide. HPLC provided resolution of the individual extractable metabolites. In an attempt to identify these metabolites, two DTPA-amino acid sequences were synthesized: DTPA-D-Phe-Cys and DTPA-D-Phe. Under the conditions used for metabolite analysis, In-111-DTPA-D-Phe-Cys-OH eluted at 14.6 min and In-111-DTPA-D-Phe-OH eluted at 7.0 min. Each of these standard sequences was combined with the soluble portion of the organ homogenate and was shown by 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 and In-111-DTPA-D-Phe-OH. The In-111-DTPA-D-Phe-Cys-OH was further degraded 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 concluded that at longer time points (>2 h postinjection) a significant amount 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.