title: The in vivo disposition and in vitro transmembrane transport of two model radiometabolites of DOTA-conjugated receptor-specific peptides labelled with (177) Lu.
abstract: 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.
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Department of Pharmacology and Toxicology, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Volková
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Department of Pharmacology and Toxicology, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Mandíková
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Department of Pharmacology and Toxicology, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Bárta
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Department of Pharmacology and Toxicology, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Navrátilová
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Department of Pharmacology and Toxicology, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: Alice
authors.initials: A
authors.lastname: Lázníčková
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Department of Pharmacology and Toxicology, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: František
authors.initials: F
authors.lastname: Trejtnar
mesh_terms: D000818:Animals; D056831:Coordination Complexes / Q000737:chemistry / Q000493:pharmacokinetics*; D004285:Dogs; D005755:Gastrins / Q000737:chemistry / Q000493:pharmacokinetics*; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013004:Somatostatin / Q000031:analogs & derivatives / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: C000610676:177Lu-DOTA-Glu-Ala-Tyr; C000610675:177Lu-DOTA-Phe; C000610677:177Lu-DOTA-minigastrin 11; D056831:Coordination Complexes; D005755:Gastrins; D009842:Oligopeptides; D027701:Organic Cation Transport Proteins; D019275:Radiopharmaceuticals; C008530:minigastrin; D010649:Phenylalanine; D013004:Somatostatin
keywords: minigastrins; nephrotoxicity; organic anion transporter; organic cation transporter; pharmacokinetics; somatostatin analogues