On the Importance of Metabolic Stability to Achieve High Oral Exposures for Cyclic Peptides

Following up on a previous publication in which we reported a high liver first pass effect in rats for the cyclic peptide (1) [Ala-Leu-NMe-D-Leu-NMe-Leu-Leu-D-Pro], we decided to investigate the type of metabolites formed and to suggest solutions to this problem. As a result of a bile duct cannulation study in rats and subsequent derivatization of this peptide by an isolated Cyp-enzyme, several hydroxylated variants were identified. Cyclopropyl-Ala (Cpa) residues as surrogates for Leu alleviated metabolism at these particular side chains. Significant progress was achieved, when in addition the D-Pro residue was exchanged by 4,4 difluoro-D-Pro (DiF-D-Pro). Albeit the Ala was kept constant in this process, in the corresponding in-vivo studies in rats, peptide (6) [Ala-Cpa-NMe-D-Cpa-NMe-Cpa-Cpa-4,4 difluro-D-Pro] exhibited mM exposures at 3mg/kg and an absolute oral bioavailability of > 90%. Thus, we emphasize the importance of controlling metabolism to achieve significant systemic exposure upon oral administration and suggest the Cpa- and DiF-D-Pro residues as metabolically stable isosteres for Leu, and D-Pro respectively.

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Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

Medicinal Chemistry ◽

10.2174/1573406416666201120102905 ◽

2020 ◽

Vol 16 ◽

Author(s):

Xi He ◽

Wenjun Hu ◽

Fanhua Meng ◽

Xingzhou Li

Keyword(s):

Plasma Concentration ◽

Broad Spectrum ◽

Plasma Concentrations ◽

Antiviral Drug ◽

Systemic Exposure ◽

Pharmacokinetic Profile ◽

Hydroxyl Group ◽

First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

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Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.8.3302-3310.2005 ◽

2005 ◽

Vol 49 (8) ◽

pp. 3302-3310 ◽

Cited By ~ 106

Author(s):

Véronique Dartois ◽

Jorge Sanchez-Quesada ◽

Edelmira Cabezas ◽

Ellen Chi ◽

Chad Dubbelde ◽

...

Keyword(s):

Cyclic Peptides ◽

Prolonged Exposure ◽

Cyclic Peptide ◽

Present Report ◽

Bacterial Load ◽

Pharmacokinetic Profile ◽

Therapeutic Window ◽

Infection Model

ABSTRACT Cyclic peptides with an even number of alternating d,l-α-amino acid residues are known to self-assemble into organic nanotubes. Such peptides previously have been shown to be stable upon protease treatment, membrane active, and bactericidal and to exert antimicrobial activity against Staphylococcus aureus and other gram-positive bacteria. The present report describes the in vitro and in vivo pharmacology of selected members of this cyclic peptide family. The intravenous (i.v.) efficacy of six compounds with MICs of less than 12 μg/ml was tested in peritonitis and neutropenic-mouse thigh infection models. Four of the six peptides were efficacious in vivo, with 50% effective doses in the peritonitis model ranging between 4.0 and 6.7 mg/kg against methicillin-sensitive S. aureus (MSSA). In the thigh infection model, the four peptides reduced the bacterial load 2.1 to 3.0 log units following administration of an 8-mg/kg i.v. dose. Activity against methicillin-resistant S. aureus was similar to MSSA. The murine pharmacokinetic profile of each compound was determined following i.v. bolus injection. Interestingly, those compounds with poor efficacy in vivo displayed a significantly lower maximum concentration of the drug in serum and a higher volume of distribution at steady state than compounds with good therapeutic properties. S. aureus was unable to easily develop spontaneous resistance upon prolonged exposure to the peptides at sublethal concentrations, in agreement with the proposed interaction with multiple components of the bacterial membrane canopy. Although additional structure-activity relationship studies are required to improve the therapeutic window of this class of antimicrobial peptides, our results suggest that these amphipathic cyclic d,l-α-peptides have potential for systemic administration and treatment of otherwise antibiotic-resistant infections.

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Nonclinical Toxicology and Toxicokinetic Profile of an Oral Lanthionine Synthetase C-Like 2 (LANCL2) Agonist, BT-11

International Journal of Toxicology ◽

10.1177/1091581819827509 ◽

2019 ◽

Vol 38 (2) ◽

pp. 96-109 ◽

Cited By ~ 4

Author(s):

Andrew Leber ◽

Raquel Hontecillas ◽

Victoria Zoccoli-Rodriguez ◽

Marion Ehrich ◽

Jennifer Davis ◽

...

Keyword(s):

Human Peripheral Blood ◽

Clinical Signs ◽

Systemic Exposure ◽

Micronucleus Assay ◽

Peripheral Blood Lymphocytes ◽

In Vivo Studies ◽

Repeat Dose ◽

Toxicity Studies ◽

Oral Doses

BT-11 is an orally active, gut-restricted investigational therapeutic targeting the lanthionine synthetase C-like 2 pathway with lead indications in ulcerative colitis (UC) and Crohn disease (CD), 2 manifestations of inflammatory bowel disease (IBD). In 5 mouse models of IBD, BT-11 is effective at oral doses of 8 mg/kg. BT-11 was also efficacious at nanomolar concentrations in primary human samples from patients with UC and CD. BT-11 was tested under Good Laboratory Practice conditions in 90-day repeat-dose general toxicity studies in rats and dogs, toxicokinetics, respiratory, cardiovascular and central nervous system safety pharmacology, and genotoxicity studies. Oral BT-11 did not cause any clinical signs of toxicity, biochemical or hematological changes, or macroscopic or microscopic changes to organs in 90-day repeat-dose toxicity studies in rats and dogs at doses up to 1,000 mg/kg/d. Oral BT-11 resulted in low systemic exposure in both rats (area under the curve exposure from t = 0 to t = 8 hours [AUC0-8] of 216 h × ng/mL) and dogs (650 h × ng/mL) and rapid clearance with an average half-life of 3 hours. BT-11 did not induce changes in respiratory function, electrocardiogram parameters, or behavior with single oral doses of 1,000 mg/kg/d. There was no evidence of mutagenic or genotoxic potential for BT-11 up to tested limit doses using an Ames test, chromosomal aberration assay in human peripheral blood lymphocytes, or micronucleus assay in rats. Therefore, nonclinical studies show BT-11 to be a safe and well-tolerated oral therapeutic with potential as a potent immunometabolic therapy for UC and CD with no-observed adverse effect level >1,000 mg/kg in in vivo studies.

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Effect of preexposure to dietary benzo[a]pyrene (BP) on the first-pass metabolism of BP by the intestine of toadfish (Opsanus tau): in vivo studies using portal vein-catheterized fish

Toxicology and Applied Pharmacology ◽

10.1016/0041-008x(88)90385-7 ◽

1988 ◽

Vol 92 (2) ◽

pp. 255-265 ◽

Cited By ~ 48

Author(s):

Peter A. Van Veld ◽

John S. Patton ◽

Richard F. Lee

Keyword(s):

Portal Vein ◽

In Vivo Studies ◽

Opsanus Tau ◽

First Pass Metabolism ◽

First Pass ◽

Pass Metabolism

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Engineering pro-angiogenic peptides using stable, disulfide-rich cyclic scaffolds

Blood ◽

10.1182/blood-2011-06-359141 ◽

2011 ◽

Vol 118 (25) ◽

pp. 6709-6717 ◽

Cited By ~ 146

Author(s):

Lai Y. Chan ◽

Sunithi Gunasekera ◽

Sonia T. Henriques ◽

Nathalie F. Worth ◽

Sarah-Jane Le ◽

...

Keyword(s):

Trypsin Inhibitor ◽

Cyclic Peptides ◽

Cyclic Peptide ◽

Therapeutic Potential ◽

Therapeutic Angiogenesis ◽

Peptide Fragments ◽

Drug Candidates ◽

Therapeutic Uses ◽

Momordica Cochinchinensis

Abstract Fragments from the extracellular matrix proteins laminin and osteopontin and a sequence from VEGF have potent proangiogenic activity despite their small size (< 10 residues). However, these linear peptides have limited potential as drug candidates for therapeutic angiogenesis because of their poor stability. In the present study, we show that the therapeutic potential of these peptides can be significantly improved by “grafting” them into cyclic peptide scaffolds. Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) and sunflower trypsin inhibitor-1 (SFTI-1), naturally occurring, plant-derived cyclic peptides of 34 and 14 residues, respectively, were used as scaffolds in this study. Using this approach, we have designed a peptide that, in contrast to the small peptide fragments, is stable in human serum and at nanomolar concentration induces angiogenesis in vivo. This is the first report of using these scaffolds to improve the activity and stability of angiogenic peptide sequences and is a promising approach for promoting angiogenesis for therapeutic uses.

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Design and Evaluation of Ornidazole Sustained release Dental Inserts

Current Drug Metabolism ◽

10.2174/1389200222666210222152940 ◽

2021 ◽

Vol 22 ◽

Author(s):

Sunchu Harika ◽

Y. Shravan Kumar ◽

Y. Madhusudhan Rao ◽

Pavani Sriram ◽

Uma Shankar

Keyword(s):

Sustained Release ◽

Release Kinetics ◽

Fickian Diffusion ◽

In Vivo Studies ◽

Drug Candidate ◽

Content Uniformity ◽

Pocket Depth ◽

Weight Variation ◽

First Pass

Aim & Background: Ornidazole an antimicrobial drug used to treat certain types of vaginal, urinary tract, and interstitial infections. The objective of this study is to formulate and evaluate the dental inserts by using drug candidate to sustained release of drug to improve patient compliance, reduce dosing frequency, better therapeutic efficacy and fewer side effects, reduce the risk of dose dumping as well as also to avoid the first-pass metabolism. Materials & Method: The dental inserts were prepared using various polymers and in combination with the different ratios of polymers. The evaluation parameters like thickness, drug content, content uniformity, moisture reuptake, weight variation, swelling studies, and erosion studies of the optimized inserts were studied. The in-vivo studies were conducted for determining the reduction of pocket depth in human volunteers. Results: The system containing ethylcellulose and hydroxyl methyl propyl cellulose K100M (4:1) formulation F6 was optimized because drug release was sustained up to 120 hrs with respect to other formulations. Optimized formulation follows first-order kinetics and Peppas release kinetics via fickian diffusion. There was no swelling, itching, irritation and the reduction of pocket depth was absorbed in in-vivo studies. Conclusion: The study concluded that dental inserts can extend the release of Ornidazole for many hours also enhanced bioavailability, further it also helps in avoiding the first-pass effect. The observations of in vivo studies were, there was no itching, irritation, swelling, and reduction in pocket depth was observed.

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Monitoring the Fate of Orally Administered PLGA Nanoformulation for Local Delivery of Therapeutic Drugs

Pharmaceutics ◽

10.3390/pharmaceutics11120658 ◽

2019 ◽

Vol 11 (12) ◽

pp. 658 ◽

Cited By ~ 3

Author(s):

Lucia Morelli ◽

Sara Gimondi ◽

Marta Sevieri ◽

Lucia Salvioni ◽

Maria Guizzetti ◽

...

Keyword(s):

Oral Administration ◽

Systemic Exposure ◽

Plga Nanoparticles ◽

In Vivo Studies ◽

Cancer Drug ◽

Therapeutic Drugs ◽

Human Disorders ◽

Carcinoma Colon

One of the goals of the pharmaceutical sciences is the amelioration of targeted drug delivery. In this context, nanocarrier-dependent transportation represents an ideal method for confronting a broad range of human disorders. In this study, we investigated the possibility of improving the selective release of the anti-cancer drug paclitaxel (PTX) in the gastro-intestinal tract by encapsulating it into the biodegradable nanoparticles made by FDA-approved poly(lactic-co-glycolic acid) (PLGA) and coated with polyethylene glycol to improve their stability (PLGA-PEG-NPs). Our study was performed by combining the synthesis and characterization of the nanodrug with in vivo studies of pharmacokinetics after oral administration in mice. Moreover, fluorescent PLGA-nanoparticles (NPs), were tested both in vitro and in vivo to observe their fate and biodistribution. Our study demonstrated that PLGA-NPs: (1) are stable in the gastric tract; (2) can easily penetrate inside carcinoma colon 2 (CaCo2) cells; (3) reduce the PTX absorption from the gastrointestinal tract, further limiting systemic exposure; (4) enable PTX local targeting. At present, the oral administration of biodegradable nanocarriers is limited because of stomach degradation and the sink effect played by the duodenum. Our findings, however, exhibit promising evidence towards our overcoming these limitations for a more specific and safer strategy against gastrointestinal disorders.

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A Cyclic Peptide Epitope of an Under-Explored VEGF-B Loop 1 Demonstrated In Vivo Anti-Angiogenic and Anti-Tumor Activities

Frontiers in Pharmacology ◽

10.3389/fphar.2021.734544 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lei Wang ◽

Meng Xu ◽

Haofeng Hu ◽

Lun Zhang ◽

Fei Ye ◽

...

Keyword(s):

Cyclic Peptides ◽

Cyclic Peptide ◽

Umbilical Vein ◽

Chorioallantoic Membrane ◽

Docking Study ◽

Human Gastric Cancer ◽

Nude Mouse Model ◽

Peptide Epitope

Pathological angiogenesis is mainly initiated by the binding of abnormal expressed vascular endothelial growth factors (VEGFs) to their receptors (VEGFRs). Blocking the VEGF/VEGFR interaction is a clinically proven treatment in cancer. Our previous work by epitope scan had identified cyclic peptides, mimicking the loop 1 of VEGF-A, VEGF-B and placental growth factor (PlGF), inhibited effectively the VEGF/VEGFR interaction in ELISA. We described here the docking study of these peptides on VEGFR1 to identify their binding sites. The cellular anti-angiogenic activities were examined by inhibition of VEGF-A induced cell proliferation, migration and tube formation in human umbilical vein endothelial cells (HUVECs). The ability of these peptides to inhibit MAPK/ERK1/2 signaling pathway was examined as well. On chick embryo chorioallantoic membrane (CAM) model, a cyclic peptide named B-cL1 with most potent in vitro activity showed important in vivo anti-angiogenic effect. Finally, B-cL1 inhibited VEGF induced human gastric cancer SGC-7901 cells proliferation. It showed anti-tumoral effect on SGC-7901 xenografted BALB/c nude mouse model. The cyclic peptides B-cL1 constitutes an anti-angiogenic peptide drug lead for the design of new and more potent VEGFR antagonists in the treatment of angiogenesis related diseases.

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