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

The effect of replacement of the N,N-chelating ligand 1,10-phenanthroline (phen) in the Ir(III) pentamethylcyclopentadienyl (Cp*) complex [(η(5)-Cp*)(Ir)(phen)Cl](+) (2) with the C,N-chelating ligand 7,8-benzoquinoline (bq) to give [(η(5)-Cp*)(Ir)(bq)Cl] (1) on the cytotoxicity of these Cp*Ir(III) complexes toward cancer cell lines was investigated. Complex 2 is inactive, similar to other Cp*Ir(III) complexes containing the N,N-chelating ligands. In contrast, a single atom change (C(-) for N) in the chelating N,N ligand resulted in potency in human ovarian carcinoma cisplatin-sensitive A2780 cells, and, strikingly, 1 is active in the cisplatin-resistant human breast cancer MCF-7 and A2780/cisR cells. Replacement of the N,N-chelating ligand with the C,N-chelating ligand gives rise to increased hydrophobicity, leading to higher cellular accumulation, higher DNA-bound iridium in cells and higher cytotoxicity. The pathways involved in cellular accumulation of 1 have been further explored and compared with conventional cisplatin. The results show that both energy-independent passive diffusion and energy-dependent transport play a role in accumulation of 1. Further results were consistent with involvement of p-glycoprotein, multidrug resistance-associated protein 1 and glutathione metabolism in the efflux of 1. In contrast, the internalization of 1 mediated by the endocytotic uptake pathway(s) seems less likely. Understanding the factors which contribute to the mechanism of cellular accumulation of this Ir(III) complex can now lead to the design of structurally similar metal complexes for antitumor chemotherapy.

• MeSH
• antitumorózní látky chemie   farmakokinetika   farmakologie   MeSH
• chelátory chemie   farmakokinetika   farmakologie   MeSH
• chemorezistence MeSH
• cisplatina farmakologie   MeSH
• iridium chemie   farmakokinetika   farmakologie   MeSH
• komplexní sloučeniny chemie   farmakokinetika   farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH