Published online Jul 27, 2018. doi: 10.4254/wjh.v10.i7.496
Peer-review started: March 12, 2018
First decision: March 29, 2018
Revised: April 6, 2018
Accepted: April 9, 2018
Article in press: April 9, 2018
Published online: July 27, 2018
Processing time: 139 Days and 1.1 Hours
To overcome the hazardous effects on liver caused by long-term use of antitubercular agent isoniazid (INH) by developing a novel hepatoprotective prodrug strategy by conjugating INH with aminothiols as antioxidant promoities for probable synergistic effect.
INH was conjugated with N-acetyl cysteine (NAC) and N-(2)-mercaptopropionyl glycine using the Schotten-Baumann reaction and with L-methionine using Boc-anhydride through a biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis, and in vitro and in vivo release studies were carried out using HPLC. Their hepatoprotective potential was evaluated in male Wistar rats by performing liver function tests, measuring markers of oxidative stress and carrying out histopathology studies.
Prodrugs were found to be stable in acidic (pH 1.2) and basic (pH 7.4) buffers and in rat stomach homogenates, whereas they were hydrolysed significantly (59.43%-94.93%) in intestinal homogenates over a period of 6 h. Upon oral administration of prodrug NI to rats, 52.4%-61.3% INH and 47.4%-56.8% of NAC were recovered in blood in 8-10 h. Urine and faeces samples pooled over a period of 24 h exhibited 1.3%-2.5% and 0.94%-0.9% of NAC, respectively, without any presence of intact NI or INH. Prodrugs were biologically evaluated for hepatoprotective activity. All the prodrugs were effective in abating oxidative stress and re-establishing the normal hepatic physiology. The effect of prodrug of INH with NAC in restoring the levels of the enzymes superoxide dismutase and glutathione peroxidase and abrogating liver damage was noteworthy especially.
The findings of this investigation demonstrated that the reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment.
Core tip: To overcome the deleterious effects caused by long-term use of isoniazid (INH), a novel hepatoprotective prodrug strategy was developed by integrating the antioxidant property of aminothiols with INH moiety to improve its therapeutic safety. The anticipated prodrugs were synthesized using facile method of synthesis, wherein aminothiols were tethered to the INH molecule via biocleavable amide linkage. Upon hepatoprotective potential assessment, the prodrug NI displayed noteworthy effects, whereas prodrugs MGI and MI exhibited moderate effects. The findings of this study strongly suggest that concept-based design of hepatoprotective prodrugs can be applied effectively in reversing toxic effects of INH and its metabolites on liver.