Amelioration of hepatotoxicity by biocleavable aminothiol chimeras of isoniazid: Design, synthesis, kinetics and pharmacological evaluation

Figure 1 Scheme of synthesis for NI and MGI.

Figure 2 Scheme of synthesis for MI.

Figure 3 Proposed activation mechanism of prodrugs.

Figure 4 In vivo pharmacokinetics after oral administration of the prodrug NI (blood). NI: Prodrug of INH and N-acetyl cysteine.

Figure 5 Effect of prodrugs on markers of liver function and oxidative stress and biochemical parameters. Average of six readings; One-way ANOVA followed by Dunnett’s multiple comparison test, statistical significance considered at ^aP < 0.05, ^bP < 0.01, ^eP < 0.001 and ns: non-significant, when vs INH-treated group. H: Healthy control; INH: Isoniazid; NI: Prodrug of INH and N-acetyl cysteine; MGI: Prodrug of INH and N-(2-mercaptopropionyl) glycine; MI: Prodrug of INH and L-methionine; INH + NAC: Physical mixture of INH + N-acetyl cysteine; INH + MPG: Physical mixture of INH + N-(2-mercaptopropionyl) glycine; INH + Met: Physical mixture of INH and L-methionine.

Figure 6 Photomicrographs of haematoxylin and eosin-stained histological sections of normal, isoniazid-intoxicated, prodrugs- and physical mixtures-treated rat livers.