Investigation of disposition for TAK-448, a synthetic peptide of kisspeptin analog, in rats and dogs using the radiolabeled TAK-448 suitable for pharmacokinetic study. (3rd July 2019)

• Record Type: Journal Article
• Authors: Moriya, Yuu; Kogame, Akifumi; Tagawa, Yoshihiko; Morohashi, Akio; Kondo, Takahiro; Asahi, Satoru
• Is Part Of: Xenobiotica. Volume 49:Number 7(2019:Jul.)
• Page Start: 833
• Page End: 839
• Publication Date: 2019-07-03
• Subjects: TAK-448 (RVT-602) -- disposition -- rat -- dog -- kisspeptin agonist; Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.1080/00498254.2018.1499152
• Languages: English
• ISSNs: 0049-8254

Abstract

Abstract: Disposition of 2-( N -acetyl-d -tyrosyl- trans -4-hydroxy-l -prolyl-l -asparaginyl-l -threonyl-l -phenylalanyl) hydrazinocarbonyl-L-leucyl- N ω -methyl-l -arginyl-l -tryptophanamide monoacetate (TAK-448, RVT-602), a synthetic kisspeptin analog, was investigated after parenteral dosing of radiolabeled TAK-448 ([d -Tyr- 14 C]TAK-448) to rats and dogs, and it was confirmed if the radiolabeling position atd -Tyr was eligible for assessment of in vivo disposition. Dosed radioactivity was rapidly and well absorbed after subcutaneous administration and an appreciable amount of unchanged TAK-448 (TAK-448F) and a hydrolyzed metabolite, M-I, were detected in the plasma of rats and dogs. After intravenous administration of [d -Tyr- 14 C]TAK-448 to rats, the radioactivity widely distributed to tissues with relatively higher concentrations in kidney and urinary bladder. The radioactivity was decreased rapidly from the tissues. After subcutaneous administration of [d -Tyr- 14 C]TAK-448 to rats and dogs, the dosed radioactivity was almost completely recovered by 48 and 72 h in rats and dogs, respectively, and most of the radioactivity was excreted in urine after extensive metabolism in the two species. These results suggest that TAK-448 has an acceptable pharmacokinetic profile for clinical evaluation and development, and demonstrate that the synthesized [D-Tyr- 14 C]TAK-448 used in this study represents a favorable labeling position to evaluate disposition properties of this compound.