In vivo metabolism of the radiolabelled receptor-specific peptides has been described; however, information regarding the pharmacokinetic behaviour of the degradation products within the body is very scarce. The present study was designed to obtain new knowledge on the disposition and elimination of low-molecular radiometabolites of receptor-specific peptides in the organism and to reveal the potential involvement of selected membrane transport mechanisms in the cellular uptake of radiometabolites, especially in the kidney. The study compared pharmacokinetics of two radiometabolites: a final metabolite of somatostatin analogues, (177)Lu-DOTA-DPhe, and a tripeptide metabolite of (177)Lu-DOTA-minigastrin 11, (177)Lu-DOTA-DGlu-Ala-Tyr. Their pharmacokinetics was compared with that of respective parent (177)Lu-radiopeptide. Both radiometabolites exhibited relative rapid clearing from most body tissues in rats in vivo along with predominant renal excretion. The long-term renal retention of the smaller radiometabolite (177)Lu-DOTA-DPhe was lower than that of (177)Lu-DOTA-DGlu-Ala-Tyr. An uptake of (177)Lu-DOTA-DPhe by human renal influx transporter organic cation transporter 2 was found in vitro in a cellular model. The study brings the first experimental data on the in vivo pharmacokinetics of radiometabolites of receptor-specific somatostatin and gastrin analogues. The found results may indicate a negative correlation between the degree of decomposition of the parent peptide chain and the renal retention of the metabolite.
- MeSH
- buňky MDCK MeSH
- fenylalanin analogy a deriváty chemie farmakokinetika MeSH
- gastriny chemie farmakokinetika MeSH
- HeLa buňky MeSH
- komplexní sloučeniny chemie farmakokinetika MeSH
- krysa rodu rattus MeSH
- ledviny metabolismus MeSH
- lidé MeSH
- oligopeptidy chemie farmakokinetika MeSH
- potkani Wistar MeSH
- proteiny přenášející organické kationty metabolismus MeSH
- psi MeSH
- radiofarmaka chemie farmakokinetika MeSH
- somatostatin analogy a deriváty chemie MeSH
- tkáňová distribuce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
INTRODUCTION: Radiolabeled receptor-targeting peptides are a useful tool for the diagnostic imaging and radiotherapy of some malignancies. However, the retention of radioactivity in the kidney may result in renal radiotoxic injury. This study seeks to evaluate the role of endocytic receptor megalin, renal SLC influx transporters and fluid phase endocytosis (FPE) in the cellular accumulation of radiolabeled peptides. METHODS: In vitro transport cellular studies using megalin ligands (RAP, albumin), fluid phase endocytosis (FPE) inhibitor rottlerin and low temperature were employed to evaluate the transport mechanisms of the peptides. Cells transfected with hOAT1 or hOCT2 were used to analyze the role of these SLC transporters. Somatostatin ((177)Lu-DOTA-[Tyr(3)]octreotate, (177)Lu-DOTA-[1-Nal(3)]octreotide), gastrin ((177)Lu-DOTA-sargastrin) and bombesin ((177)Lu-DOTA-[Pro(1),Tyr(4)]bombesin, (177)Lu-DOTA-[Lys(3)]bombesin, (177)Lu-PCTA-[Lys(3)]bombesin) analogues were involved in the study. RESULTS: RAP, albumin and low temperature decreased the accumulation of all the studied peptides significantly. With one exception, rottlerin caused the concentration dependent inhibition of the cellular accumulation of the radiopeptides. No significant differences in the uptake of the peptides between the control cells and those transfected with hOAT1 or hOCT2 were observed. CONCLUSION: The study showed that active transport mechanisms are decisive for the cellular accumulation in all tested (177)Lu-labeled somatostatin, gastrin and bombesin analogues. Besides receptor-mediated endocytosis by megalin, FPE participates significantly in the uptake. The tested types of renal SLC transporters are not involved in this process.
- MeSH
- biologický transport MeSH
- bombesin chemie metabolismus MeSH
- buněčná membrána metabolismus MeSH
- endocytóza * MeSH
- gastriny chemie metabolismus MeSH
- HeLa buňky MeSH
- izotopové značení MeSH
- lidé MeSH
- lutecium * MeSH
- peptidové hormony chemie metabolismus MeSH
- prasata MeSH
- přenašeče organických aniontů nezávislé na sodíku metabolismus MeSH
- protein 1 přenášející organické anionty metabolismus MeSH
- somatostatin chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Horizonty diabetologie ; díl 1 Folia Ethologica ; I
247 s. : il., tab. ; 22 cm
- MeSH
- fylogeneze MeSH
- glukagon chemie MeSH
- inzulin chemie MeSH
- Langerhansovy ostrůvky MeSH
- pankreas cytologie MeSH
- somatostatin chemie MeSH
- vývojová biologie MeSH
- Publikační typ
- monografie MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- diabetologie
- biochemie
- cytologie, klinická cytologie
- Klíčová slova
- REMESTYP,
- MeSH
- ezofageální a žaludeční varixy komplikace MeSH
- gastrointestinální krvácení farmakoterapie terapie MeSH
- lidé MeSH
- nitroglycerin aplikace a dávkování terapeutické užití MeSH
- oktreotid aplikace a dávkování farmakologie chemie MeSH
- portální hypertenze farmakoterapie komplikace MeSH
- somatostatin aplikace a dávkování farmakologie chemie MeSH
- vasopresiny analogy a deriváty aplikace a dávkování farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
177 s. : tab., grafy ; 22 cm
- MeSH
- inzulin chemie MeSH
- lipidy MeSH
- peptidy MeSH
- somatostatin chemie MeSH
- Publikační typ
- vysokoškolské kvalifikační práce MeSH
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- biochemie
