Effects of backbone cyclization on the pharmacokinetics and drug efficiency of the orally active analgesic conotoxin cVc1.1
Chronic pain is an undertreated epidemic affecting quality of life in at least 20% of the global population, and CNS-related side effects, tolerance, and addiction are common features of current medications. α-Conotoxin Vc1.1 potently elicits prolonged analgesia in preclinical chronic constriction i...
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Format: | Article |
Language: | English |
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Elsevier
2021-06-01
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Series: | Medicine in Drug Discovery |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2590098621000087 |
id |
doaj-e60af3d636f34e9cace11a1df3b3f934 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Aaron G. Poth Francis C.K. Chiu Sofie Stalmans Brett R. Hamilton Yen-Hua Huang David M. Shackleford Rahul Patil Thao T. Le Meng-Wei Kan Thomas Durek Evelien Wynendaele Bart De Spiegeleer Andrew K. Powell Deon J. Venter Richard J. Clark Susan A. Charman David J. Craik |
spellingShingle |
Aaron G. Poth Francis C.K. Chiu Sofie Stalmans Brett R. Hamilton Yen-Hua Huang David M. Shackleford Rahul Patil Thao T. Le Meng-Wei Kan Thomas Durek Evelien Wynendaele Bart De Spiegeleer Andrew K. Powell Deon J. Venter Richard J. Clark Susan A. Charman David J. Craik Effects of backbone cyclization on the pharmacokinetics and drug efficiency of the orally active analgesic conotoxin cVc1.1 Medicine in Drug Discovery conotoxin cyclic peptides pharmacokinetics bioavailability drug efficiency index |
author_facet |
Aaron G. Poth Francis C.K. Chiu Sofie Stalmans Brett R. Hamilton Yen-Hua Huang David M. Shackleford Rahul Patil Thao T. Le Meng-Wei Kan Thomas Durek Evelien Wynendaele Bart De Spiegeleer Andrew K. Powell Deon J. Venter Richard J. Clark Susan A. Charman David J. Craik |
author_sort |
Aaron G. Poth |
title |
Effects of backbone cyclization on the pharmacokinetics and drug efficiency of the orally active analgesic conotoxin cVc1.1 |
title_short |
Effects of backbone cyclization on the pharmacokinetics and drug efficiency of the orally active analgesic conotoxin cVc1.1 |
title_full |
Effects of backbone cyclization on the pharmacokinetics and drug efficiency of the orally active analgesic conotoxin cVc1.1 |
title_fullStr |
Effects of backbone cyclization on the pharmacokinetics and drug efficiency of the orally active analgesic conotoxin cVc1.1 |
title_full_unstemmed |
Effects of backbone cyclization on the pharmacokinetics and drug efficiency of the orally active analgesic conotoxin cVc1.1 |
title_sort |
effects of backbone cyclization on the pharmacokinetics and drug efficiency of the orally active analgesic conotoxin cvc1.1 |
publisher |
Elsevier |
series |
Medicine in Drug Discovery |
issn |
2590-0986 |
publishDate |
2021-06-01 |
description |
Chronic pain is an undertreated epidemic affecting quality of life in at least 20% of the global population, and CNS-related side effects, tolerance, and addiction are common features of current medications. α-Conotoxin Vc1.1 potently elicits prolonged analgesia in preclinical chronic constriction injury and chronic visceral hypersensitivity models of neuropathic pain. A backbone-cyclized variant, cVc1.1, exhibits superior in vitro stability and is orally active, but its in vivo half-life and disposition, both critical in informing drug candidate progression, remain unexplored. Here, we investigate the pharmacological influence of the peptidic bridge differentiating linear and cyclic Vc1.1 in various preclinical PK/PD rodent models. While previous in vitro studies had indicated cyclization conferred increased stability for cVc1.1, in vivo the peptides exhibited similar half-lives and oral bioavailabilities. The ratios of free drug exposure metrics (Cmax × fu,p and AUC0-inf × fu,p) following oral dosing vs. their respective in vitro IC50s at the GABAB receptor were comparable for Vc1.1 and cVc1.1, indicating similar drug efficiency indexes. MALDI imaging, radiolabel, and LC-MS biodistribution studies of cVc1.1 in rodents demonstrated that the intact cyclopeptide and several metabolites persist in the GI tract for at least 4 h, long after the plasma levels of the intact peptide had fallen below the target IC50. Biodistribution analyses of IV administered 125I-labelled cVc1.1 revealed accumulation primarily in the kidneys consistent with renal elimination, and combined with insignificant uptake in brain, suggested a low likelihood of CNS-related side effects. |
topic |
conotoxin cyclic peptides pharmacokinetics bioavailability drug efficiency index |
url |
http://www.sciencedirect.com/science/article/pii/S2590098621000087 |
work_keys_str_mv |
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doaj-e60af3d636f34e9cace11a1df3b3f9342021-05-28T05:04:18ZengElsevierMedicine in Drug Discovery2590-09862021-06-0110100087Effects of backbone cyclization on the pharmacokinetics and drug efficiency of the orally active analgesic conotoxin cVc1.1Aaron G. Poth0Francis C.K. Chiu1Sofie Stalmans2Brett R. Hamilton3Yen-Hua Huang4David M. Shackleford5Rahul Patil6Thao T. Le7Meng-Wei Kan8Thomas Durek9Evelien Wynendaele10Bart De Spiegeleer11Andrew K. Powell12Deon J. Venter13Richard J. Clark14Susan A. Charman15David J. Craik16Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane 4072, AustraliaCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, AustraliaDrug Quality and Registration (DruQuaR) Group, Ghent University, Ghent 9000, BelgiumCenter for Microscopy and Microanalysis, The University of Queensland, Brisbane 4072, Australia; Mater Health Services, Pathology Department, South Brisbane 4101, AustraliaInstitute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane 4072, AustraliaCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, AustraliaCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, AustraliaInstitute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane 4072, AustraliaInstitute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane 4072, AustraliaInstitute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane 4072, AustraliaDrug Quality and Registration (DruQuaR) Group, Ghent University, Ghent 9000, BelgiumDrug Quality and Registration (DruQuaR) Group, Ghent University, Ghent 9000, BelgiumCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, AustraliaMater Health Services, Pathology Department, South Brisbane 4101, AustraliaSchool of Biomedical Sciences, The University of Queensland, Brisbane 4072, AustraliaCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, AustraliaInstitute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane 4072, Australia; Corresponding author at: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.Chronic pain is an undertreated epidemic affecting quality of life in at least 20% of the global population, and CNS-related side effects, tolerance, and addiction are common features of current medications. α-Conotoxin Vc1.1 potently elicits prolonged analgesia in preclinical chronic constriction injury and chronic visceral hypersensitivity models of neuropathic pain. A backbone-cyclized variant, cVc1.1, exhibits superior in vitro stability and is orally active, but its in vivo half-life and disposition, both critical in informing drug candidate progression, remain unexplored. Here, we investigate the pharmacological influence of the peptidic bridge differentiating linear and cyclic Vc1.1 in various preclinical PK/PD rodent models. While previous in vitro studies had indicated cyclization conferred increased stability for cVc1.1, in vivo the peptides exhibited similar half-lives and oral bioavailabilities. The ratios of free drug exposure metrics (Cmax × fu,p and AUC0-inf × fu,p) following oral dosing vs. their respective in vitro IC50s at the GABAB receptor were comparable for Vc1.1 and cVc1.1, indicating similar drug efficiency indexes. MALDI imaging, radiolabel, and LC-MS biodistribution studies of cVc1.1 in rodents demonstrated that the intact cyclopeptide and several metabolites persist in the GI tract for at least 4 h, long after the plasma levels of the intact peptide had fallen below the target IC50. Biodistribution analyses of IV administered 125I-labelled cVc1.1 revealed accumulation primarily in the kidneys consistent with renal elimination, and combined with insignificant uptake in brain, suggested a low likelihood of CNS-related side effects.http://www.sciencedirect.com/science/article/pii/S2590098621000087conotoxincyclic peptidespharmacokineticsbioavailabilitydrug efficiency index |