Pharmacokinetics and renal handling of Tc-99m-labeled peptides

Tc-99m-labeled peptides, particularly those of a lipophilic nature, are oft en excreted through the hepatobiliary system, and the subsequent accumulati on in the intestine may obscure receptor-mediated uptake in tumor sites in the pelvis. We have therefore explored the route and rate of excretion of a small series of Tc-labeled peptides to shed some light on the mechanisms t hat influence the clearance of these agents. Methods: Pharmacokinetic param eters, biodistribution, routes of elimination of Tc-99m-complexes of 3 mode l tetrapeptides-namely, acetyl-N-Gly-Gly-Cys-Gly (AGGCG), acetyl-N-Ser-Ser- Cys-Gly (ASSCG), and acetyl-N-Gly-Gly-Cys-Lys (AGGCL)-were determined in ra ts in vivo. Renal handling of the complexes was studied in the perfused rat kidney. Results: After intravenous injection, a relatively fast disappeara nce of the complexes from blood was found. Although the parameters of distr ibution in all 3 chelates were very similar, the elimination rate of Tc-99m -AGGCG was higher than those of Tc-99m-ASSCG and Tc-99m-AGGCL. The Tc compl exes under study were distributed mainly to the excretory organs (kidneys a nd liver), and no specific accumulation in other organs or tissues was foun d. Most of the radioactivity after intravenous administration of the chelat es was rapidly eliminated through the urine, but a significant amount was a lso excreted through the feces, in the following order among the 3 chelates : Tc-99m-AGGCL < Tc-99m-ASSCG < Tc-99m-AGGCG. Different proportions of glom erular filtration and secretion in renal tubules of the complexes were foun d in the perfused rat kidney. Elimination by glomerular filtration was domi nant only in the case of Tc-99m-AGGCL, whereas the rate of filtration of Tc -99m-AGGCG was very low because of its high protein binding. Various rates of secretion into renal tubules were shown for all 3 agents. This renal exc retion pathway was decisive in Tc-99m-AGGCG and lowest in Tc-99m-AGGCL. Tc- 99m-ASSCG was eliminated by both mechanisms at similar rates. Conclusion: T hese studies shaw that increasing the hydrophilic nature or reducing the ne gative charge of the peptides will reduce their hepatobiliary excretion, wh ereas the incorporation of suitable peptide sequences permits them to explo it efficient routes of renal excretion, such as tubular secretion, thereby optimizing the pattern of biodistribution of these radiopharmaceuticals.