TY - JOUR AU - Alrushaid, Samaa AU - Davies, Neal M. AU - Anderson, Judy E. AU - Le, Tyson AU - Yáñez, Jaime A. AU - Maayah, Zaid H. AU - El-Kadi, Ayman O.S. AU - Rachid, Ousama AU - Sayre, Casey L. AU - Löbenberg, Raimar AU - Burczynski, Frank J. PY - 2018/03/30 Y2 - 2024/03/28 TI - Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies JF - Journal of Pharmacy & Pharmaceutical Sciences JA - J Pharm Pharm Sci VL - 21 IS - 1s SE - Pharmaceutical Sciences; Original Research Articles DO - 10.18433/J3MS8H UR - https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/29683 SP - 1s-18s AB - <p><strong>PURPOSE: </strong>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 <em>in silico</em>, <em>in vitro</em>, and <em>in vivo </em>approaches to characterize MyoNovin and examine its safety, biodistribution, and feasibility for drug delivery.<strong> </strong><strong>METHODS:</strong> <em>In silico</em> software packages were used to predict the physicochemical and biopharmaceutical properties of MyoNovin. <em>In vitro</em> 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.<strong> </strong><strong>RESULTS: </strong>MyoNovin showed relatively high lipophilicity with a LogP value of 3.49, a 20-fold higher skin permeability (19.89 cm/s*10<sup>7</sup>) compared to guaifenesin (0.66 cm/s*10<sup>7</sup>), and ~10-fold higher effective jejunal permeability (2.24 cm/s*10<sup>4</sup>) compared to guaifenesin (0.26 cm/s*10<sup>4</sup>). <em>In vitro,</em> MyoNovinwas not cytotoxic to cardiomyocytes at concentrations below 8 μM and did not inhibit CYP3A4 or show antioxidant activity. <em>In vivo,</em> MyoNovin had a short half-life (t<sub>1/2</sub>) of 0.16 h, and a volume of distribution V<sub>ss</sub> of 0.62 L/kg. Biomarkers of MyoNovincardiac and renal toxicity did not differ significantly from baseline control levels.<strong>CONCLUSIONS:</strong> 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.</p><p> </p><p>This article is open to <strong>POST-PUBLICATION REVIEW</strong>. Registered readers (see “For Readers”) may <strong>comment</strong> by clicking on ABSTRACT on the issue’s contents page.</p> ER -