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Pharmacokinetics and Renal Handling of ^99mTc-Labeled Peptides

Faculty of Pharmacy, Charles University in Prague, Hradec Kralove, Czech Republic
St. Bartholomew's Hospital, London, United Kingdom

Correspondence: For correspondence or reprints contact: Frantisek Trejtnar, PhD, Charles University in Prague, Faculty of Pharmacy, Heyrovskeho 1203, CZ-500 05 Hradec Kralove, Czech Republic.

ABSTRACT

^99mTc-labeled peptides, particularly those of a lipophilic nature, are often excreted through the hepatobiliary system, and the subsequent accumulation 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 that influence the clearance of these agents. Methods: Pharmacokinetic parameters, biodistribution, routes of elimination of ^99mTc-complexes of 3 model 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 rats in vivo. Renal handling of the complexes was studied in the perfused rat kidney. Results: After intravenous injection, a relatively fast disappearance of the complexes from blood was found. Although the parameters of distribution in all 3 chelates were very similar, the elimination rate of ^99mTc-AGGCG was higher than those of ^99mTc-ASSCG and ^99mTc-AGGCL. The Tc complexes under study were distributed mainly to the excretory organs (kidneys and liver), and no specific accumulation in other organs or tissues was found. Most of the radioactivity after intravenous administration of the chelates was rapidly eliminated through the urine, but a significant amount was also excreted through the feces, in the following order among the 3 chelates: ^99mTc-AGGCL < ^99mTc-ASSCG < ^99mTc-AGGCG. Different proportions of glomerular filtration and secretion in renal tubules of the complexes were found in the perfused rat kidney. Elimination by glomerular filtration was dominant only in the case of ^99mTc-AGGCL, whereas the rate of filtration of ^99mTc-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 excretion pathway was decisive in ^99mTc-AGGCG and lowest in ^99mTc-AGGCL. ^99mTc-ASSCG was eliminated by both mechanisms at similar rates. Conclusion: These studies show that increasing the hydrophilic nature or reducing the negative charge of the peptides will reduce their hepatobiliary excretion, whereas the incorporation of suitable peptide sequences permits them to exploit efficient routes of renal excretion, such as tubular secretion, thereby optimizing the pattern of biodistribution of these radiopharmaceuticals.

Key Words: tetrapeptides • ^99mTc • pharmacokinetics • peptide complexes