Research and development of new dosage form of isoniazid with low adverse reaction

Isoniazid (INH), a widely used drug in the prophylaxis and treatment of tuberculosis, has been found to be associated with 1 to 2% risk of severe and potentially fatal hepatotoxicity. Studies suggest that cytochrome P450 2E1 (CYP2E1) could play an important role in the pathogenesis of INH-induced hepatotoxicity. Recently, many studies presented flavonoids or ingredients of herbal medicines may regulate liver P450 isozymes. HUCHE010 is a flavonoid compound found in many vegetables, fruits, seeds or roots of plants, and herbal medicines. Purpose of this study is using CYP2E1 inhibitor, HUCHE010 to prove the concept that CYP2E1 inhibitor can reduce or even eradicate INH combine Rifampicin (RIF), CYP2E1 stimulator, induced hepatotoxicity. Three groups of 129/sv mice were studies with 3 weeks dosing period: Hepatotoxic group was given INH/RIF 50/100mg/kg/day, Hepato-protective group was given INH/RIF combined with HUCHE010, and Vehicle group was given vehicle only. To assess the hepatotoxicity, we employed galactose single point (GSP), a quantitative measurement of liver function, histopathologic features of the liver tissues, and general liver function assement of AST and ALT. The INH/RIF-induced hepatotoxicity were significantly associated in AST (from 90±15 to 571±295 U/L, p<0.001), ALT (40±5 to 364±192 U/L, p<0.001), and GSP (from 184±24 to 866±339mg/L, p<0.001). Hepato-protective pretreatment of HUCHE010 could reduced INH/RIF-induced hepatotoxicity (significantly reduced GSP to 401±178mg/L). These results show that INH/RIF-induced hepatotoxicity can be reduced by CYP2E1 inhibitor, HUCHE010.

Fig.1: Experimental Procedure