Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies

Authors

  • Samaa Alrushaid College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. http://orcid.org/0000-0001-7705-9025
  • Neal M. Davies Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB. CANADA.
  • Judy E. Anderson Department of Biological Sciences, Faculty of Science, and Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
  • Tyson Le College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
  • Jaime A. Yáñez YARI International Group, New Brunswick, NJ 08901 and INDETEC Corp., Lima Perú.
  • Zaid H. Maayah Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB. CANADA.
  • Ayman O.S. El-Kadi Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB. CANADA.
  • Ousama Rachid Pharmaceutical Sciences Section, College of Pharmacy, Qatar University, Doha, Qatar.
  • Casey L. Sayre College of Pharmacy, Roseman University of Health Sciences, South Jordan.
  • Raimar Löbenberg Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB. CANADA.
  • Frank J. Burczynski College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. Department of Pharmacology & Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

DOI:

https://doi.org/10.18433/J3MS8H

Abstract

PURPOSE: MyoNovin is a novel skeletal muscle-regenerating compound developed through synthesis of two nitro groups onto a guaifenesin backbone to deliver nitric oxide to skeletal muscle with a potential to treat muscle atrophy. The purpose of this study was to utilize in silico, in vitro, and in vivo approaches to characterize MyoNovin and examine its safety, biodistribution, and feasibility for drug delivery. METHODS: In silico software packages were used to predict the physicochemical and biopharmaceutical properties of MyoNovin. In vitro cardiotoxicity was assessed using human cardiomyocytes (RL-14) while effects on CYP3A4 metabolic enzyme and antioxidant activity were examined using commercial kits. A novel HPLC assay was developed to measure MyoNovin concentration in serum, and delineate initial pharmacokinetic and acute toxicity after intravenous administration (20 mg/kg) to male Sprague-Dawley rats. RESULTS: MyoNovin showed relatively high lipophilicity with a LogP value of 3.49, a 20-fold higher skin permeability (19.89 cm/s*107) compared to guaifenesin (0.66 cm/s*107), and ~10-fold higher effective jejunal permeability (2.24 cm/s*104) compared to guaifenesin (0.26 cm/s*104). In vitro, MyoNovinwas not cytotoxic to cardiomyocytes at concentrations below 8 μM and did not inhibit CYP3A4 or show antioxidant activity. In vivo, MyoNovin had a short half-life (t1/2) of 0.16 h, and a volume of distribution Vss of 0.62 L/kg. Biomarkers of MyoNovincardiac and renal toxicity did not differ significantly from baseline control levels.CONCLUSIONS: The predicted high lipophilicity and skin permeability of MyoNovin render it a potential candidate for transdermal administration while its favourable intestinal permeation suggests it may be suitable for oral administration. Pharmacokinetics following IV administration of MyoNovin were delineated for the first time in a rat model. Preliminary single 20 mg/kg dose assessment of MyoNovin suggest no influenceon cardiac troponin or β-N-Acetylglucosaminidase.

 

This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Downloads

Download data is not yet available.

Author Biography

Samaa Alrushaid, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

PhD candidate 

College of Pharmacy

Rady Faculty of Health Sciences 

Downloads

Published

2018-03-30

How to Cite

Alrushaid, S., Davies, N. M., Anderson, J. E., Le, T., Yáñez, J. A., Maayah, Z. H., El-Kadi, A. O., Rachid, O., Sayre, C. L., Löbenberg, R., & Burczynski, F. J. (2018). Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies. Journal of Pharmacy &Amp; Pharmaceutical Sciences, 21(1s), 1s–18s. https://doi.org/10.18433/J3MS8H

Issue

Section

Pharmaceutical Sciences; Original Research Articles