Pharmacokinetic characterization of kalata B1 and related therapeutics built on the cyclotide scaffold.

Autor: Poth AG; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address: a.poth@imb.uq.edu.au., Huang YH; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address: y.huang@imb.uq.edu.au., Le TT; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address: thaothithu.le@ecu.edu.au., Kan MW; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address: a.kan@imb.uq.edu.au., Craik DJ; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address: d.craik@imb.uq.edu.au.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics [Int J Pharm] 2019 Jun 30; Vol. 565, pp. 437-446. Date of Electronic Publication: 2019 May 04.
DOI: 10.1016/j.ijpharm.2019.05.001
Abstrakt: Oral activity has been described for cyclotide-containing traditional medicines, and demonstrated for reengineered cyclotides bearing grafted therapeutic epitopes, highlighting their potential for translation to the clinic. Here we report preclinical pharmacokinetic parameters for the prototypic cyclotide kalata B1 (kB1) and two orally active grafted analogues, ckb-KAL and ckb-KIN, to provide the first in vivo dose-exposure metrics for cyclotides. Native and grafted kB1 molecules exhibited multiple compartment kinetics and measurable but limited oral bioavailability of similar magnitude to several orally administered peptide drugs in the clinic. Cyclotides are mostly associated with the central compartment, and display small (0.07-0.13 L kg -1 for kB1 and ckb-KIN) to moderate (1 L kg -1 for ckb-KAL) steady state volumes of distribution. This study provides new data essential to the evaluation of cyclotides as therapeutics, validating them as a viable drug design scaffold with tunable pharmacokinetic properties.
(Copyright © 2019. Published by Elsevier B.V.)
Databáze: MEDLINE
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