Biodistribution and Pharmacokinetics of PEG-10kDa-Cholecystokinin-10 in Rats After Different Routes of Administration

Fabian      Leon-Tamariz; Isabelle      Verbaeys; Maurits      Van Boven; Marcel      De Cuyper; Johan      Buyse; Peter      de Witte; Alfons      Verbruggen; Marnix      Cokelaere

Abstract

Cholecystokinin, produced in the proximal small intestine, is a short acting satiating peptide hormone. CCK-10, before and after mono-iodination, was previously coupled to 10kDa polyethylene glycol (PEG). The formed conjugates PEG10kDa-CCK-10 and PEG10kDa-[127I]-CCK-10 show after i.p. administration to rats a sustained food intake reduction during 8h in comparison to 2h for free CCK-10. The present study examined the blood pharmacokinetics of this pharmacological interesting molecule by means of PEG10kDa-[123I]-CCK-10 following intravenous, intraperitoneal, intramuscular and nasal administration and the biodistribution after i.p. administration. HPLC analysis with radiometric detection allowed the differentiation between inorganic iodide and the intact tracer in blood. Blood kinetics after i.v. injection was fitted to a bi-exponential with a distribution half-life of 15 min and with an elimination half-life of 8 hours for intact PEG10kDa-[123I]-CCK-10. The biodistribution studies showed a higher accumulation of the tracer for all administration routes in organs expressing CCK receptors localized in the gastrointestinal tract such as pancreas, duodenum and small intestine. No indication of blood brain barrier crossing for the conjugate could be observed independently of the administration route. Main clearance was via the urinary pathway.

Keywords: CCK-10, PEG10kDa-CCK-10, PEG10kDa-[123I]-CCK-10, satiety, biodistribution, pharmacokinetics

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