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.
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.