Novel Thioester Prodrug of N-acetylcysteine for Odor Masking and Bioavailability Enhancement

Author(s): Neha V. Bhilare, Suneela S. Dhaneshwar, Akanksha J. Sinha, Amit D. Kandhare, Subhash L. Bodhankar

Journal Name: Current Drug Delivery

Volume 13 , Issue 4 , 2016

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Background: The mucolytic N-acetylcysteine (NAC) is used to control the excessive mucus secretion if mucus is the underlying cause of broncho-constriction. Its major drawbacks are poor bioavailability due to extensive first pass effect, poor lipophilicity, high protein binding and offensive odor.

Methods: For minimizing above shortcomings of NAC, in present study thioester (A1) prodrug of NAC was synthesized by conventional as well as microwave-assisted methods. Release studies of A-1 were carried out using HPLC and pharmacological evaluation was performed in ovalbumin-induced model of pulmonary inflammation in Sprague dawley rats.

Results: A-1 was found to be stable in HCl buffer, phosphate buffer, stomach homogenates but furnished 30% NAC in 6h and 1.7% of NAC in 4h when incubated with small intestinal and liver homogenates respectively. Upon oral administration of A-1 to rats, 4.85% NAC was detected in blood at 8h. Urine samples pooled over a period of 24h exhibited 0.75% NAC while negligible concentration was found in 24 h pooled samples of feces.

Conclusion: The findings of this preliminary investigation demonstrated significant effects of thioester prodrug A-1 as compared to NAC through reduction of lung inflammation, airway eosinophilia and reversal of lung function parameters in ovalbumin- challenged rats at half the equimolar dose of NAC. Interestingly masking thiol group through thioester formation resulted in odorless prodrug. We propose that thioester prodrug using palmitic acid as a carrier is a promising strategy to enhance bioavailability of NAC by increasing its lipophilicity/ absorption and minimizing its first pass metabolism.

Keywords: N-acetylcysteine, odor masking, ovalbumin, palmitic acid, poor bioavailability, thioester prodrug, thiol.

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Article Details

Year: 2016
Published on: 04 September, 2015
Page: [611 - 620]
Pages: 10
DOI: 10.2174/1567201812666150904144607
Price: $65

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