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

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

Volume: 13 Issue: 4

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

Affiliation:

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

Abstract: 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.

Cite this article as:

V. Bhilare Neha, S. Dhaneshwar Suneela, J. Sinha Akanksha, D. Kandhare Amit and L. Bodhankar Subhash, Novel Thioester Prodrug of N-acetylcysteine for Odor Masking and Bioavailability Enhancement, Current Drug Delivery 2016; 13 (4) . https://dx.doi.org/10.2174/1567201812666150904144607